Amino acid derivatives

ABSTRACT

A compound of the formula (1):  
                 
 
     [wherein R 1  is (substituted) alkyl, alkoxy, phenyl, hetero ring etc.; A is bond, CO, SO 2 ; R 2  is H, (substituted) alkyl etc.; D is alkylene etc.; E is COO, OCO, O, S, SO, SO 2  etc.; R 3  is (substituted) alkyl, carbocyclic ring, hetero ring; J is O, NR 16  (R 16  is H, substituted alkyl); R 4  is (substituted) alkyl, carbocyclic ring, hetero ring.] or non-toxic salt thereof, and an N-type calcium channel blocker comprising it as an active ingredient.  
     The compounds of the formula (I) possess an inhibitory action on N-type calcium channel, so they are useful as agent for the prevention and/or treatment of cerebral infarct, transient ischemic attack, encephalomyelopathy after cardiac operation, spinal angiopathy, hypertension with stress, neurosis or epilepsy etc. or agent for the treatment of pain.

FIELD OF THE INVENTION

[0001] The present invention relates to an amino acid derivative of theformula (I), a process for the preparation thereof, and a pharmaceuticalcomposition comprising it as an active ingredient.

[0002] More particularly, it relates to amino acid derivatives of theformula (I)

[0003] (wherein all the symbols are the same meanings as hereinafterdescribed.), non-toxic salts thereof, and the hydrates thereof,processes for the preparation thereof, and N-type calcium channelblocker comprising them.

BACKGROUND OF THE INVENTION

[0004] Calcium ion has been known as an intracellular messenger forsignal transduction, and it is suggested that various physiologicalevents are triggered by the elevation of intracellular calciumconcentration. Calcium influx from extracellular fluid is one of themechanisms for the elevation of intracellular calcium concentration. Thegate of calcium influx is the voltage-dependent calcium channels. Thevoltage-dependent calcium channel is opened by the polarization ofplasma membrane, and calcium ion influxes from extracellular fluid intothe cell selectively through the channel according to theelectrochemical gradient. The voltage-dependent calcium channels areclassified into N-, L-, P-, Q- and T-type at present. It is known thatL- and T-type calcium channels are distributed in the various tissuesubiquitously, and especially, L-type calcium channel is enriched in thesmooth muscle cells or the cardiac muscle cells. On the other hand, N-and P-type calcium channels are mainly located in the nervous system andrelated to the neurotransmitter release. This neurotransmitter is storedin synaptic vesicles of nerve terminals at resting state. When actionpotential by signal transmission on nerve is conducted in pre-synapticfiber and reaches to the nerve terminal, the voltage-dependent calciumchannels are activated and then, calcium ion influxes into the nerveterminals. By these mechanisms, synaptic vesicles are fused withpre-synaptic membrane, and neurotransmitters in the vesicles arereleased. The released neurotransmitters are related to signaltransmission in synapse due to binding to their receptors inpost-synaptic membrane. From the above, an N-type calcium channelblocker is thought to be effective on various diseases induced by anexcessive release of neurotransmitter. For example, it may be useful asagent for the prevention and/or treatment of cerebral infarct (J. Cereb.Blood Flow Metab., Vol. 17, 421-429, 1997), transient ischemic attack,encephalomyelopathy after cardiac operation, spinal angiopathy,hypertension with stress (Science., 239, 57-61, 1988), neurosis orepilepsy etc. or agent for the treatment of pain (for example, acutepain, chronic pain, pain after operation, cancer pain, neuralgia, paincaused by infection etc.) (Pain, 60, 83-90, 1995).

[0005] The venoms isolated from the genus Conus, ω-conotoxin GVIA,MVIIA, are well known as N-type calcium channel blockers.

[0006] But, these ω-conotoxins are peptidic compounds, so it is expectedthat they have various problems (for example, they are not absorbed intothe living body easily.). Therefore, there is a demand for arrangementof these blockers to non-peptidic compounds namely to small-molecule.There are some reports relate to small-molecule as follows:

[0007] For example, it is described in the specification of JapanesePatent Kokai Hei 8-217671 that glycine derivatives of the formula (A)

R^(1A)CH(OCOR^(2A)) CH₂CONHCH₂CO₂H (A)

[0008] (wherein R^(1A) and R^(2A) are, same or different, C1-19 straightor branched alkyl, or C2-19 straight or branched alkenyl.) and saltsthereof are N-type calcium channel blocker.

[0009] It is described In the specification of EP 805147 that thecompounds of the formula (B)

[0010] (wherein R^(1B) is alkyl, R^(2B) is hydrogen, optionallysubstituted alkyl, optionally substituted aryl or optionally substitutedheteroaryl, R³ is hydrogen, CN, X^(B) is bond or SO₂, R^(4B), R^(5B),R^(6B), R^(8B), R^(9B) and R^(10B) are each hydrogen or alkyl, A^(B) isCH or Y^(B)CO (in which Y^(B) is bond.), R^(7B) is C-a substituent ofamino acid or ester thereof, R^(6B) and R^(7B) together form C3-5alkylene chain optionally substituted by C1-alkyl or hydroxy, orCH₂—Z^(B)—CH₂ (in which Z^(B) is CO, S, SO, SO₂.), R^(7B) and R^(8B)together form C3-5 alkylene chain optionally substituted by C1-4 alkylor hydroxy, B^(B) is CON(R²¹⁸), mB is 0˜2, R^(11B) is hydrogen or alkyl,R^(12B) is hydrogen, alkyl, optionally substituted aryl or optionallysubstituted heteroaryl, R^(13B) is alkyl, optionally substituted aryl,or optionally substituted heteroaryl, R^(12B) and R^(13B) together formC3-8 cycloalkyl.), the salts thereof, or the ester thereof are calciumchannel modulator (necessary part is extracted in the explanation of thegroup.).

[0011] Also, it is described in the specification of Japanese PatentKokai Sho 61-200950 that the compound of the formula (C)

[0012] (wherein R^(C) and R^(1C) each independently, is lower alkyl,aryl-lower alkyl or phenyl optionally substituted by one or moreelectron-withdrawing or electron-donating group, R^(2C) and R^(3C) eachindependently, is hydrogen, lower alkyl, aryl-lower alkyl or phenyloptionally substituted with one or more electron-withdrawing orelectron-donating group, and nC is 1˜4.) and pharmaceutically acceptablesalts thereof are anti-convulsant agent.

DISCLOSURE OF THE INVENTION

[0013] As the result of energetic investigations in order to findcompounds possessing an N-type calcium channel blockery action, thepresent inventors have found that the purpose has been accomplished bythe compound of the formula (I). Most of compounds of the formula (I)are new.

[0014] The present invention relates to:

[0015] 1) an N-type calcium channel blocker comprising, as an activeingredient, an amino acid derivative of the formula (I)

[0016] [wherein R¹ is

[0017] 1) C1-15 alkyl,

[0018] 2) C1-8 alkoxy,

[0019] 3) phenyl,

[0020] 4) C3-8 cycloalkyl,

[0021] 5) hetero ring,

[0022] 6) C1-4 alkyl substituted by phenyl, C3-8 cycloalkyl, or heteroring,

[0023] 7) C1-4 alkoxy substituted by phenyl, C3-8 cycloalkyl, or heteroring, or

[0024] 8) C2-4 alkenyl substituted by phenyl, C3-8 cycloalkyl, or heteroring (with proviso that, all phenyl, C3-8 cycloalkyl and hetero ring inR¹ group may be substituted by 1˜3 of substituent selected from thefollowing (i)˜(xi);

[0025] (i) C1-4 alkyl,

[0026] (ii) C1-4 alkoxy,

[0027] (iii) phenyl,

[0028] (iv) phenoxy,

[0029] (v) benzyloxy,

[0030] (vi) —SR⁵ (in which R⁵ is hydrogen or C1-4 alkyl.),

[0031] (vii) C2-5 acyl,

[0032] (viii) halogen,

[0033] (ix) C1-4 alkoxycarbonyl,

[0034] (x) nitro,

[0035] (xi) —NR⁶R⁷ (in which R⁵ and R⁷ each independently, is hydrogen,C1-4 alkyl or C1-4 alkoxycarbonyl, or R⁶ and R⁷ taken together with thenitrogen atom to which they are attached may represent 5˜7 memberedsaturated hetero ring containing another one nitrogen atom or one oxygenatom.).);

[0036] A is bond, —CO— or —SO₂—;

[0037] R² is hydrogen or C1-4 alkyl optionally substituted by onephenyl;

[0038] D is C1-4 alkylene or C2-4 alkenylene;

[0039] E is

[0040] 1) —COO—,

[0041] 2) —OCO—,

[0042] 3) —CONR⁸— (in which R⁸ is hydrogen or C1-4 alkyl.),

[0043] 4) —NR⁹CO— (in which R⁹ is hydrogen or C1-4 alkyl.),

[0044] 5) —O—,

[0045] 7) —SO—,

[0046] 8) —SO₂—,

[0047] 9) —NR¹⁰— (in which R¹⁰ is hydrogen or C1-4 alkyl.),

[0048] 10) —CO—,

[0049] 11) —SO₂NR¹¹— (in which R¹¹ is hydrogen or C1-4 alkyl.), or

[0050] 12) —NR¹²SO₂— (in which R¹² is hydrogen or C1-4 alkyl.);

[0051] R is

[0052] 1) carbocyclic ring,

[0053] 2) hetero ring, or

[0054] 3) C1-4 alkyl substituted by carbocyclic ring or hetero ring(with proviso that, all carbocyclic ring and hetero ring in R³, may besubstituted by 1˜3 of substituent selected from the following (i)˜(xi);

[0055] (i) C1-4 alkyl,

[0056] (ii) C1-4 alkoxy,

[0057] (iii) phenyl,

[0058] (iv) phenoxy,

[0059] (v) benzyloxy,

[0060] (vi) —SR¹³ (in which R¹³ is hydrogen or C1-4 alkyl.),

[0061] (vii) C2-5 acyl,

[0062] (viii) halogen,

[0063] (ix) C0-4 alkoxycarbonyl,

[0064] (x) nitro,

[0065] (xi) —NR¹⁴R¹⁵ (in which R¹⁴ and R¹⁵ each independently, ishydrogen, C1-4 alkyl or C1-4 alkoxycarbonyl, or R¹⁴ and R¹⁵ takentogether with the nitrogen atom to which they are attached may represent5˜7 membered saturated hetero ring containing another one nitrogen atomor one oxygen atom.).);

[0066] J is —O— or —NR¹⁶— (in which R¹⁶ is hydrogen or C1-4 alkyl.);

[0067] R⁴ is

[0068] 1) C1-8 alkyl,

[0069] 2) carbocyclic ring,

[0070] 3) hetero ring,

[0071] 4) C1-8 alkyl substituted by 1˜3 of substituent selected from thefollowing (i)˜(v);

[0072] (i) carbocyclic ring,

[0073] (ii) hetero ring,

[0074] (iii) COOR¹⁷ (in which R¹⁷ is hydrogen or C1-4 alkyl substitutedby one phenyl (in which phenyl may be substituted by C1-4 alkoxy.),

[0075] (iv) SR¹⁸ (in which R¹⁸ is hydrogen or C1-4 alkyl.),

[0076] (v) OR¹⁹ (in which R¹⁹ is hydrogen or C1-4 alkyl.), or

[0077] when J represents —NR¹⁶— group, R⁴ and R¹⁶ taken together withthe nitrogen atom to which they are attached may represent hetero ring(with proviso that, all carbocyclic ring and hetero ring, and heteroring represented by R⁴ and R¹⁶ taken together with the nitrogen atom towhich they are attached may be substituted by 1˜3 of substituentselected from the following (i)˜(xi);

[0078] (i) C1-4 alkyl,

[0079] (ii) C1-4 alkoxy,

[0080] (iii) phenyl,

[0081] (iv) phenoxy,

[0082] (v) benzyloxy,

[0083] (vi) —SR²⁰ (in which R²⁰ is hydrogen or C1-4 alkyl.),

[0084] (vii) C2-5 acyl,

[0085] (viii) halogen,

[0086] (ix) C1-4 alkoxycarbonyl,

[0087] (x) nitro,

[0088] (xi) —NR²¹R²² (in which R²¹ and R²² each independently, ishydrogen, C1-4 alkyl or C1-4 alkoxycarbonyl, or R²¹ and R²² takentogether with the nitrogen atom to which they are attached may represent5˜7 membered saturated hetero ring containing another one nitrogen atomor one oxygen atom.).).],

[0089] non-toxic salt thereof, or a hydrate thereof, and

[0090] 2) an amino acid derivative of the formula (I)

[0091] [wherein R¹ is

[0092] 1) C1-15 alkyl,

[0093] 2) C1-8 alkoxy,

[0094] 3) phenyl,

[0095] 4) C3-8 cycloalkyl,

[0096] 5) hetero ring,

[0097] 6) C1-4 alkyl substituted by phenyl, C3-8 cycloalkyl, or heteroring,

[0098] 7) C1-4 alkoxy substituted by phenyl, C3-8 cycloalkyl, or heteroring, or

[0099] 8) C2-4 alkenyl substituted by phenyl, C3-8 cycloalkyl, or heteroring (with proviso that, all phenyl, C3-8 cycloalkyl and hetero ring inR¹ group may be substituted by 1˜3 of substituent selected from thefollowing (i)˜(xi);

[0100] (i) C1-4 alkyl,

[0101] (ii) C1-4 alkoxy,

[0102] (iii) phenyl,

[0103] (iv) phenoxy,

[0104] (v) benzyloxy,

[0105] (vi) —SR⁵ (in which R⁵ is hydrogen or C1-4 alkyl.),

[0106] (vii) C2-5 acyl,

[0107] (viii) halogen,

[0108] (ix) C1-4 alkoxycarbonyl,

[0109] (x) nitro,

[0110] (xi) —NR⁶R⁷ (in which R⁶ and R⁷ each independently, is hydrogen,C1-4 alkyl or C1-4 alkoxycarbonyl, or R⁶ and R⁷ taken together with thenitrogen atom to which they are attached may represent 5˜7 memberedsaturated hetero ring containing another one nitrogen atom or one oxygenatom.).);

[0111] A is bond, —CO— or —SO₂—;

[0112] R² is hydrogen or C1-4 alkyl optionally substituted by onephenyl;

[0113] D is C1-4 alkylene or C2-4 alkenylene;

[0114] E is

[0115] 1) —COO—,

[0116] 2) —OCO—,

[0117] 3) —CONR⁸— (in which R⁸ is hydrogen or C1-4 alkyl.),

[0118] 4) —NR⁹CO— (in which R⁹ is hydrogen or C1-4 alkyl.),

[0119] 5) —O—,

[0120] 6) —S—,

[0121] 7) —SO—,

[0122] 8) —SO₂—,

[0123] 9) —NR¹⁰— (in which R¹⁰ is hydrogen or C1-4 alkyl.),

[0124] 10) —CO—,

[0125] 11) —SO₂NR¹¹— (in which R¹¹ is hydrogen or C1-4 alkyl.), or

[0126] 12) —NR²SO₂— (in which R¹² is hydrogen or C1-4 alkyl.);

[0127] R³ is

[0128] 1) carbocyclic ring,

[0129] 2) hetero ring, or

[0130] 3) C1-4 alkyl substituted by carbocyclic ring or hetero ring(with proviso that, all carbocyclic ring and hetero ring in R³, may besubstituted by 1˜3 of substituent selected from the following (i)˜(xi);

[0131] (i) C1-4 alkyl,

[0132] (ii) C1-4 alkoxy,

[0133] (iii) phenyl,

[0134] (iv) phenoxy,

[0135] (v) benzyloxy,

[0136] (vi) —SR¹³ (in which R¹³ is hydrogen or C1-4 alkyl.),

[0137] (vii) C2-5 acyl,

[0138] (viii) halogen,

[0139] (ix) C1-4 alkoxycarbonyl,

[0140] (x) nitro,

[0141] (xi) —NR¹⁴R¹⁵ (in which R¹⁴ and R¹⁵ each independently, ishydrogen, C1-4 alkyl or C1-4 alkoxycarbonyl, or R¹⁴ and R¹⁵ takentogether with the nitrogen atom to which they are attached may represent5˜7 membered saturated hetero ring containing another one nitrogen atomor one oxygen atom.).);

[0142] J is —O— or —NR¹⁶— (in which R¹⁶ is hydrogen or C1-4 alkyl.);

[0143] R⁴ is

[0144] 1) C1-8 alkyl,

[0145] 2) carbocyclic ring,

[0146] 3) hetero ring,

[0147] 4) C1-8 alkyl substituted by 1˜3 of substituent selected from thefollowing (i)˜(v);

[0148] (i) carbocyclic ring,

[0149] (ii) hetero ring,

[0150] (iii) COOR¹⁷ (in which R¹⁷ is hydrogen or C1-4 alkyl substitutedby one phenyl (in which phenyl may be substituted by C1-4 alkoxy.),

[0151] (iv) SR¹⁸ (in which R¹⁸ is hydrogen or C1-4 alkyl.),

[0152] (v) OR¹⁹ (in which R¹⁹ is hydrogen or C1-4 alkyl.), or

[0153] when J represents —NR¹⁶— group, R⁴ and R¹⁶ taken together withthe nitrogen atom to which they are attached may represent hetero ring(with proviso that, all carbocyclic ring and hetero ring, and heteroring represented by R⁴ and R¹⁶ taken together with the nitrogen atom towhich they are attached may be substituted by 1˜3 of substituentselected from the following (i)˜(xi);

[0154] (i) C1-4 alkyl,

[0155] (ii) C1-4 alkoxy,

[0156] (iii) phenyl,

[0157] (iv) phenoxy,

[0158] (v) benzyloxy,

[0159] (vi) —SR²⁰ (in which R²⁰ is hydrogen or C1-4 alkyl.),

[0160] (vii) C2-5 acyl,

[0161] (viii) halogen,

[0162] (ix) C1-4 alkoxycarbonyl,

[0163] (x) nitro,

[0164] (xi) —NR²¹R²² (in which R²¹ and R²² each independently, ishydrogen, C1-4 alkyl or C1-4 alkoxycarbonyl, or R²¹ and R²² takentogether with the nitrogen atom to which they are attached may represent5-7 membered saturated hetero ring containing another one nitrogen atomor one oxygen atom.).).

[0165] With proviso that, the following compounds (1)-(37) are excluded:

[0166] (1)N-(2-amino-5-nitrophenyl)-3-benzyloxy-2-t-butoxycarbonylaminopropanamide,

[0167] (2) N-phenyl-3-benzyloxy-2-butoxycarbonylaminopropanamide,

[0168] (3)N-(2-aminophenyl)-3-benzyloxy-2-t-butoxycarbonylaminopropanamide,

[0169] (4)N-(4-nitrophenyl)-3-benzyloxy-2-t-butoxycarbonylaminopropanamide,

[0170] (5)N-(adamantan-2-yl)-3-benzyloxy-2-t-butoxycarbonylaminopropanamide,

[0171] (6)N-(pyridin-4-yl)-3-benzyloxy-2-t-butoxycarbonylaminopropanamide,

[0172] (7)N-(2-aminophenyl)-3-benzyloxy-2-t-butoxycarbonylaminobutanamide,

[0173] (8)N-(4-nitrophenyl)-3-benzyloxy-2-t-butoxycarbonylaminobutanamide,

[0174] (9)N-(3-bromo-4,5-dihydroisoxazol-5-ylmethyl)-3-benzyloxy-2-t-butoxycarbonylaminobutanamide,

[0175] (10)N-methyl-N-(2,6-dimethoxy-4-methylphenyl)-3-benzyloxy-2-t-butoxycarbonylaminopropanamide,

[0176] (11)N-(4-nitrophenyl)-3-benzylthio-2-t-butoxycarbonylaminopropanamide,

[0177] (12)N-(quinolin-6-yl)-3-benzylthio-2-t-butoxycarbonylaminopropanamide,

[0178] (13)N-(2-aminophenyl)-3-benzylthio-2-t-butoxycarbonylaminopropanamide,

[0179] (14)N-(adamantan-2-yl)-3-(3-ethoxycarbonylpyridin-2-ylthio)-2-t-butoxycarbonylaminopropanamide,

[0180] (15)N-methyl-N-(2-ethoxyphenyl)-3-(3-methoxycarbonylpyridin-2-yl)-2-t-butoxycarbonylaminopropanamide,

[0181] (16)N-(4-methoxycarbonylphenyl)-3-benzylthio-2-benzyloxycarbonylaminopropanamide,

[0182] (17)N-(3-bromo-4,5-dihydroisoxazol-5-ylmethyl)-3-benzylthio-2-benzyloxycarbonylaminopropanamide,

[0183] (18)N-(2-methylphenyl)-3-benzylthio-2-benzyloxycarbonylaminopropanamide,

[0184] (19)N-(3-methylphenyl)-3-benzylthio-2-benzyloxycarbonylaminopropanamide,

[0185] (20)N-(4-methylphenyl)-3-benzylthio-2-benzyloxycarbonylaminopropanamide,

[0186] (21) N-phenyl-3-benzylthio-2-benzyloxycarbonylaminopropanamide,

[0187] (22)N-(naphthalen-2-yl)-3-benzylthio-2-benzyloxycarbonylaminopropanamide,

[0188] (23)N-(naphthalen-1-yl)-3-benzylthio-2-benzyloxycarbonylaminopropanamide,

[0189] (24) N-benzyl-3-benzylthio-2-benzyloxycarbonylaminopropanamide,

[0190] (25)N-(4-chlorophenyl)-3-benzylthio-2-benzyloxycarbonylaminopropanamide,

[0191] (26)N-(4-bromophenyl)-3-benzylthio-2-benzyloxycarbonylaminopropanamide,

[0192] (27)N-(4-nitrophenyl)-3-benzylthio-2-benzyloxycarbonylaminopropanamide,

[0193] (28)N-(1,2,3,4-tetrahydronaphthalen-2-yl)-3-benzylthio-2-(4-chlorobenzyloxycarbonylamino)propanamide,

[0194] (29)N-methyl-N-(2-ethoxyphenyl)-3-(3-methoxycarbonylpyridin-2-ylthio)-2-(3,4-dichlorophenylcarbonylamino)propanamide,

[0195] (30) 3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid 4-nitrobenzyl ester,

[0196] (31) 3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.benzyl ester,

[0197] (32) 3-cycloheptyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.benzyl ester,

[0198] (33) 3-cyclooctyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.benzyl ester,

[0199] (34)3-(2-isopropyl-5-methylcyclohexyloxycarbonyl)-2-t-butoxycarbonylaminopropanoicacid.benzyl ester,

[0200] (35)N-(benzyloxycarbonylmethyl)-3-(2-isopropyl-5-methylcyclohexyloxycarbonyl)-2-t-butoxycarbonylaminopropanamide,

[0201] (36) 3-cyclohexyloxycarbonyl-2-benzyloxycarbonylaminopropanoicacid.benzyl ester, and

[0202] (37) N-phenyl-2,3-bis(benzoylamino)propanamide.],

[0203] non-toxic salt thereof, or a hydrate thereof, and

[0204] 3) processes for the preparation of an amino acid derivative ofthe formula (I) and a non-toxic salt thereof.

DETAILED EXPLANATION OF THE INVENTION

[0205] Unless otherwise specified, all isomers are included in thepresent invention. For example, alkyl, alkoxy, alkylene and alkenylenegroup include straight-chain or branched-chain ones. The double bond inalkenylene includes structure of configurations E, Z and EZ mixtures.The isomers (optical isomers) generated by asymmetric carbon atom(s) inbranched alkyl, alkoxy, alkylene and alkenylene group are also includedwithin the present invention.

[0206] In the formula (I), C1-15 alkyl group represented by R¹ meansmethyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl,decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl and theisomers thereof.

[0207] In the formula (I), C1-8 alkoxy group represented by R¹ meansmethoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy,octyloxy and the isomers thereof.

[0208] In the formula (i), C3-8 cycloalkyl group represented by R¹ orC3-8 cycloalkyl group as a substituent of C1-4 alkyl, C1-4 alkoxy orC2-4 alkenyl in R¹ group means cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl.

[0209] In the formula (I), C1-4 alkyl group represented by R⁵, R⁶, R⁷,R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁸, R¹⁹, R²⁰, R²¹ or R²²means methyl, ethyl, propyl, butyl and the isomers thereof.

[0210] In the formula (I), C1-4 alkyl group as a substituent of phenyl,C3-8 cycloalkyl or hetero ring in R¹ group, C1-4 alkyl group as asubstituent of carbocyclic ring or hetero ring in R³ or R⁴ group, orC1-4 alkyl group as a substituent of hetero ring represented by R⁴ andR¹⁶ taken together with the nitrogen atom to which they are attachedmeans methyl, ethyl, propyl, butyl and the isomers thereof.

[0211] In the formula (I), C1-4 alkyl substituted by phenyl, cycloalkylor hetero ring represented by R¹ group means methyl, ethyl, propyl,butyl and the isomers thereof substituted by phenyl, C3-8 cycloalkyl orhetero ring.

[0212] In the formula (I), C1-4 alkyl optionally substituted by onephenyl represented by R² group means methyl, ethyl, propyl, butyl andthe isomers thereof optionally substituted by one phenyl.

[0213] In the formula (I), C1-4 alkyl substituted by one phenylrepresented by R¹⁷ group means methyl, ethyl, propyl, butyl and theisomers thereof substituted by one phenyl.

[0214] In the formula (I), C1-4 alkyl substituted by carbocyclic ring orhetero ring represented by R³ group means methyl, ethyl, propyl, butyland the isomers thereof substituted by carbocyclic ring or hetero ring.

[0215] In the formula (I), C1-4 alkoxy substituted by phenyl, C3-8cycloalkyl or hetero ring means methoxy, ethoxy, propoxy, butoxy and theisomers thereof substituted by phenyl, C3-8 cycloalkyl or hetero ring.

[0216] In the formula (I), C1-4 alkoxy as a substituent of phenyl, C3-8cycloalkyl or hetero ring in R¹ group, C1-4 alkoxy as a substituent ofcarbocyclic ring or hetero ring in R³ or R⁴ group, or C1-4 alkoxy as asubstituent of hetero ring represented by R⁴ and R¹⁶ taken together withthe nitrogen atom to which they are attached means methoxy, ethoxy,propoxy, butoxy and the isomers thereof.

[0217] In the formula (I), C1-4 alkoxy as a substituent of phenyl inC1-4 alkyl substituted by one phenyl in R¹⁷ group means methoxy, ethoxy,propoxy, butoxy and the isomers thereof.

[0218] In the formula (I), C2-4 alkenyl substituted by phenyl,cycloalkyl or hetero ring group means ethenyl, propenyl, butenyl and theisomers thereof.

[0219] In the formula (I), C2-5 acyl as a substituent of phenyl, C3-8cycloalkyl or hetero ring in R¹ group, C2-5 acyl as a substituent ofcarbocyclic ring or hetero ring in R³ or R⁴ group, or C2-5 acyl as asubstituent of hetero ring represented by R⁴ and R¹⁶ taken together withthe nitrogen atom to which they are attached means acetyl, propionyl,butyryl, valeryl and the isomers thereof.

[0220] In the formula (I), halogen as a substituent of phenyl, C3-8cycloalkyl or hetero ring in R¹ group, or halogen as a substituent ofcarbocyclic ring or hetero ring in R³ or R⁴ group, or halogen as asubstituent of hetero ring represented by R⁴ and R¹⁶ taken together withthe nitrogen atom to which they are attached means fluoro, chloro, bromoand iodo.

[0221] In the formula (I), C1-4 alkoxycarbonyl represented by R⁶, R⁷,R¹⁴, R¹⁵, R²¹ or R²² means methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, butoxycarbonyl and the isomers thereof.

[0222] In the formula (i), C1-4 alkoxycarbonyl as a substituent ofphenyl, C3-8 cycloalkyl or hetero ring in R¹ group, or C1-4alkoxycarbonyl as a substituent of carbocyclic ring or hetero ring in R³or R⁴ group, or C1-4 alkoxycarbonyl as a substituent of hetero ringrepresented by R⁴ and R¹⁶ taken together with the nitrogen atom to whichthey are attached means methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, butoxycarbonyl and the isomers thereof.

[0223] In the formula (I), C1-4 alkylene represented by D group meansmethylene, ethylene, propylene, butylene and the isomers thereof.

[0224] In the formula (I), C2-4 alkenylene represented by D group meansethenylene, propenylene, butenylene and the isomers thereof.

[0225] In the formula (I), C1-8 alkyl represented by R⁴ group meansmethyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and theisomers thereof.

[0226] In the formula (I), C1-8 alkyl substituted by 1˜3 of substituentselected from (i)˜(v) represented by R⁴ group means methyl, ethyl,propyl, butyl, pentyl, hexyl, heptyl, octyl and the isomers thereofsubstituted by 1˜3 of substituent selected from (i)˜(v).

[0227] In the formula (I), 5˜7 memebered saturated hetero ringoptionally containing another one nitrogen atom or one oxygen atomrepresented by R⁶ and R⁷ taken together with the nitrogen atom to whichthey are attached, by R¹⁴ and R¹⁵ taken together with the nitrogen atomto which they are attached or by R²¹ and 22 taken together with thenitrogen atom to which they are attached means pyrrolidine, piperidine,piperazine, morpholine, perhydroazepine etc.

[0228] In the formula (I), carbocyclic ring in R³ or R⁴ means C3-10mono-, bi- and bridged carbocyclic ring. For example, C3-10 mono, bi andbridged carbocyclic ring includes cyclopropane, cyclobutane,cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane,cyclodecane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene,benzene, pentalene, indene, naphthalene, azulene, dihydronaphthalene,tetrahydronaphthalene, perhydronaphthalene, indan (dihydroindene),perhydroindene, bicyclopentane, bicyclohexane, bicycloheptane(bicyclo[2.2.1]heptane), bicycloheptene (bicyclo[2.2.1]hept-2-ene.),bicyclooctane, bicyclononane, bicyclodecane, adamantane etc.

[0229] In the formula (I), hetero ring in R¹, R³ or R⁴ group means a5˜15 memebered unsaturated, partial saturated or saturated mono-cyclicor bi-cyclic hetero ring containing 1˜2 nitrogen atom, 1˜2 oxygen atomand/or one sulfur atom. For example, a 5˜15 memebered unsaturated,partial saturated or saturated mono-cyclic or bi-cyclic hetero ringcontaining 1˜2 nitrogen atom; 1˜2 oxygen atom and/or one sulfur atomincludes pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline,pyrazolidine, piperidine, piperazine, tetrahydropyrimidine,hexahydropyrimidine, tetrahydropyridazine, hexahydropyridazine,hexahydroazepine, dihydrofuran, tetrahydrofuran, dihydropyran,tetrrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiain(dihydrothiopyran), tetrahydrothiain (tetrahydrothiopyran),dihydroxazole, tetrahydroxazole, dihydroisoxazole, tetrahydroisoxazole,dihydrothiazole, tetrahydrothiazole, dihydroisothiazole,tetraisothiazole, morpholine, thiomorpholine, indoline, isoindoline,dihydroindazole, perhydroindazole, dihydroquinoline,tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline,tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine,tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine,tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline,tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline,tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline,tetrahydrocinnoline, perhydrocinnoline, dihydrobenzoxazole,perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole,dihydrobenzimidazole, perhydrobenzimidazole, dihydrobenzoxazine,dioxaindan, benzodioxane, quinuclidine, pyrrole, imidazole, pyrazole,pyridine, pyradine, pyrimidine, pyridazine, pyridazine, azepine,diazepine, furan, pyran, oxepin, oxazepine, thiophene, thiain(thiopyran), thiepin, oxazole, isoxazole, thiazole, isothiazole,oxadiazole, oxazine, oxadiazine, oxazepin oxadiazepine, thiadiazole,thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole,benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indazole,quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline,quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole,oxatetrahydrofuran, thiazolidinone, thiazolidinedione etc.

[0230] In the formula (I), hetero ring represented by R⁴ and R¹⁶ takentogether with the nitrogen atom to which they are attached means a 5˜15memebered unsaturated, partial saturated or saturated mono-cyclic orbi-cyclic hetero ring necessarily containing one nitrogen atom andfurther containing one nitrogen atom, one oxygen atom and/or one sulfuratom. For example, a 5˜15 memebered unsaturated, partial saturated orsaturated mono-cyclic or bi-cyclic hetero ring necessarily containingone nitrogen atom and further containing one nitrogen atom, 1˜2 oxygenatom and/or one sulfur atom includes pyrroline, pyrrolidine,imidazoline, imidazolidine, pyrazoline, pyrazolidine, piperidine,piperazine, tetrahydropyrimidine, hexahydropyrimidine,tetrahydropyridazine, hexahydropyridazine, hexahydroazepine,tetrahydroxazole, tetrahydroisoxazole, tetrahydrothiazole,tetrahydroisothiazole, morpholine, thiomorpholine, indoline,isoindoline, dihydroindazole, perhydroindazole, dihydroquinoine,tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline,tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine,tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine,tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline,tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline,tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline,tetrahydrocinnoline, perhydrocinnoline, dihydrobenzoxazole,perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole,dihydrobenzimidazole, perhydrobenzimidazole, pyrrole, imidazole,pyrazole, indole, isoindole, indazole, benzimidazole etc.

[0231] Preferred R¹ is C1-8 alkoxy, phenyl, C3-8 cycloalkyl, heteroring, or C1-4 alkyl substituted by phenyl, C3-8 cycloalkyl or heteroring. Particularly, preferred R¹ is hetero ring.

[0232] Preferred A is bond or —CO—. Particularly, preferred A is —CO—.

[0233] Preferred E is —COO—, —O—, —S—, —SO— or —SO₂—. Particularly,preferred E is —S—.

[0234] Preferred carbocyclic ring represented by R³ and carbocyclic ringas substituent of C1-4 alkyl in R³ is C3-10 cycloalkyl represented bycyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane,cyclononane and cyclodecane. Particularly, preferred carbocyclic ring iscyclopentane or cyclohexane.

[0235] Preferred J is —NR¹⁶— (in which R¹⁶ is the same meaning ashereinbefore described.).

[0236] Preferred R⁴ is carbocyclic ring, hetero ring, or C1-8 alkylsubstituted by carbocyclic ring or hetero ring. Particularly, preferredR⁴ is C1-8 alkyl substituted by carbocyclic ring.

[0237] [Salts]

[0238] In the present invention, non-toxic salts includes all suchsalts.

[0239] For example, the compounds of the present invention of theformula (I) maybe converted into the corresponding salts by knownmethod. Non toxic and water-soluble salts are preferable. Suitable saltsinclude the salts of alkalimetal (sodium, potassium etc.),alkaline-earth metal (calcium, magnesium etc.), ammonium salts, salts oforganic amine which is pharmacologically permitted (tetramethylammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine,dicyclohexylamine, benzylamine, phenetylamine, piperidine,monoethanolamine, diethanolamine, tris(hydroxymethyl)amine, lysine,arginine, N-methyl-D-gulcamine etc.).

[0240] The compounds of the present invention of the formula (I) may beconverted into the corresponding acid-addition salts by known method.Non toxic and water-soluble salts are preferable. Suitable acid-additionsalts include the salts with inorganic acids such as hydrochloric acid,hydrobromic acid, sulphonic acid, phosphonic acid, nitric acid and thesalts with organic acids such as acetic acid, trifluoroacetic acid,lactic acid, tartaric acid, oxalic acid, fumaric acid, maleic acid,citric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid,benzenesulfonic acid, toluenesulfonic acid, isethionic acid, glucuronicacid and gluconic acid.

[0241] The compounds of the present invention of the formula (I) orsalts thereof may be converted into a corresponding hydrate by knownmethods.

[0242] In the compounds of the formula (I), preferred compounds are asfollows:

[0243] the compound of the formula (Ia)

[0244] (wherein all the symbols are the same meanings as hereinbeforedescribed.), the compound of the formula (Ib)

[0245] (wherein all the symbols are the same meanings as hereinbeforedescribed.), the compound of the formula (Ic)

[0246] (wherein all the symbols are the same meanings as hereinbeforedescribed.), the compound of the formula (Id)

[0247] (wherein all the symbols are the same meanings as hereinbeforedescribed.), the compound of the formula (Ie)

[0248] (wherein all the symbols are the same meanings as hereinbeforedescribed.), the compound of the formula (If)

[0249] (wherein all the symbols are the same meanings as hereinbeforedescribed.), the compound of the formula (Ig)

[0250] (wherein all the symbols are the same meanings as hereinbeforedescribed.), the compound of the formula (Ih)

[0251] (wherein all the symbols are the same meanings as hereinbeforedescribed.), non-toxic salts thereof or the hydrates thereof.

[0252] The concrete compounds are ones shown in the following Tables1-40, non-toxic salts thereof and the hydrates thereof and onesdescribed in Example. Also, the following concrete compounds include theisomers generated by asymmetric carbon atom(s), i.e., R, S and RS form.In the following each Table, Me is methyl, Boc is t-butoxycarbonyl, i-Buis isobutyl, Ac is acetyl. TABLE 1 (Ia-1)

No. R¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

[0253] TABLE 2 (Ia-2)

No. R¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

[0254] TABLE 3 (Ia-3)

No. R¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

[0255] TABLE 4 (Ia-4)

No. R¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

[0256] TABLE 5 (Ia-5)

No. R¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

[0257] TABLE 6 (Ib-1)

No. R¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

[0258] TABLE 7 (Ib-2)

No. R¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

[0259] TABLE 8 (Ib-3)

No. R¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

[0260] TABLE 9 (Ib-4)

No. R¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

[0261] TABLE 10 (Ib-5)

No. R¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

[0262] TABLE 11 (Ic-1)

No. R¹ No. R¹ No. R¹ 1

 9

17

2

10

18

3

11

19

4

12

20

5

13

21

6

14

22

7

15

23

8

16

24

[0263] TABLE 12 (Ic-2)

No. R¹ No. R¹ No. R¹ 1

 9

17

2

10

18

3

11

19

4

12

20

5

13

21

6

14

22

7

15

23

8

16

24

[0264] TABLE 13 (Ic-3)

No. R¹ No. R¹ No. R¹ 1

 9

17

2

10

18

3

11

19

4

12

20

5

13

21

6

14

22

7

15

23

8

16

24

[0265] TABLE 14 (Ic-4)

No. R¹ No. R¹ No. R¹ 1

 9

17

2

10

18

3

11

19

4

12

20

5

13

21

6

14

22

7

15

23

8

16

24

[0266] TABLE 15 (Ic-5)

No. R¹ No. R¹ No. R¹ 1

 9

17

2

10

18

3

11

19

4

12

20

5

13

21

6

14

22

7

15

23

8

16

24

[0267] TABLE 16 (Id-1)

No. R¹ No. R¹ No. R¹ 1

 9

17

2

10

18

3

11

19

4

12

20

5

13

21

6

14

22

7

15

23

8

16

24

[0268] TABLE 17 (Id-2)

No. R¹ No. R¹ No. R¹ 1

 9

17

2

10

18

3

11

19

4

12

20

5

13

21

6

14

22

7

15

23

8

16

24

[0269] TABLE 18 (Id-3)

No. R¹ No. R¹ No. R¹ 1

 9

17

2

10

18

3

11

19

4

12

20

5

13

21

6

14

22

7

15

23

8

16

24

[0270] TABLE 19 (Id-4)

No. R¹ No. R¹ No. R¹ 1

 9

17

2

10

18

3

11

19

4

12

20

5

13

21

6

14

22

7

15

23

8

16

24

[0271] TABLE 20 (Id-5)

No. R¹ No. R¹ No. R¹ 1

 9

17

2

10

18

3

11

19

4

12

20

5

13

21

6

14

22

7

15

23

8

16

24

[0272] TABLE 21 (Ie-1)

No. R¹ No. R¹ No. R¹ 1

 9

17

2

10

18

3

11

19

4

12

20

5

13

21

6

14

22

7

15

23

8

16

24

[0273] TABLE 22 (Ie-2)

No. R¹ No. R¹ No. R¹ 1

 9

17

2

10

18

3

11

19

4

12

20

5

13

21

6

14

22

7

15

23

8

16

24

[0274] TABLE 23 (Ie-3)

No. R¹ No. R¹ No. R¹ 1

 9

17

2

10

18

3

11

19

4

12

20

5

13

21

6

14

22

7

15

23

8

16

24

[0275] TABLE 24 (Ie-4)

No. R¹ No. R¹ No. R¹ 1

 9

17

2

10

18

3

11

19

4

12

20

5

13

21

6

14

22

7

15

23

8

16

24

[0276] TABLE 25 (Ie-5)

No. R¹ No. R¹ No. R¹ 1

 9

17

2

10

18

3

11

19

4

12

20

5

13

21

6

14

22

7

15

23

8

16

24

[0277] TABLE 26 (If-1)

No. R¹ No. R¹ No. R¹ 1

 9

17

2

10

18

3

11

19

4

12

20

5

13

21

6

14

22

7

15

23

8

16

24

[0278] TABLE 27 (If-2)

No. R¹ No. R¹ No. R¹ 1

 9

17

2

10

18

3

11

19

4

12

20

5

13

21

6

14

22

7

15

23

8

16

24

[0279] TABLE 28 (If-3)

No. R¹ No. R¹ No. R¹ 1

 9

17

2

10

18

3

11

19

4

12

20

5

13

21

6

14

22

7

15

23

8

16

24

[0280] TABLE 29 (If-4)

No. R¹ No. R¹ No. R¹ 1

 9

17

2

10

18

3

11

19

4

12

20

5

13

21

6

14

22

7

15

23

8

16

24

[0281] TABLE 30 (If-5)

No. R¹ No. R¹ No. R¹ 1

 9

17

2

10

18

3

11

19

4

12

20

5

13

21

6

14

22

7

15

23

8

16

24

[0282] TABLE 31 (Ig-1)

No. R¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

[0283] TABLE 32 (Ig-2)

No. R¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

[0284] TABLE 33 (Ig-3)

No. R¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

[0285] TABLE 34 (Ig-4)

No. R¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

[0286] TABLE 35 (Ig-5)

No. R¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

[0287] TABLE 36 (Ih-1)

No. R¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

[0288] TABLE 37 (Ih-2)

No. R¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

[0289] TABLE 38 (Ih-3)

No. R¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

[0290] TABLE 39 (Ih-4)

No. R¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

[0291] TABLE 40 (Ih-5)

No. R¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

[0292] [Processes for the Preparation Thereof]

[0293] (a) For the compounds of the formula (I), those in which E is—COO—, —OCO—, —CONR⁸—, —NR⁹CO—, —O—, —S—, or —CO—, i.e., the compoundsof the formula (I-A)

[0294] (wherein R¹⁻¹ is the same meaning as hereinbefore described forR¹, provided that amino group which is comprised in the grouprepresented by R¹⁻¹ may be protected, if necessary, and R³⁻¹ is the samemeaning as hereinbefore described for R³, provided that amino groupwhich is comprised in the group represented by R³⁻¹ may be protected, ifnecessary, and R⁴⁻¹ is the same meaning as hereinbefore described forR⁴, provided that —COOH, hydroxy or amino group which is comprised inthe group represented by R⁴⁻¹ may be protected, if necessary, and E¹ is—COO—, —OCO—, —CONR⁸—, —NR⁹CO—, —O—, —S— or —CO—, and the other symbolsare the same meanings as hereinbefore described.) may be prepared byamidation or esterification of a compound of formula (II)

[0295] (wherein all the symbols are the same meanings as hereinbeforedescribed.) with a compound of formula (III)

J²—R⁴⁻¹  (III)

[0296] (wherein J² is —OH, —NHR¹⁶ or hetero ring containing NH group(this hetero ring is the same meaning as hereinbefore described forhetero ring represented by R⁴, R¹⁶ and nitrogen atom which R⁴ and R¹⁶are bound to, together.), and the other symbol is the same meaning ashereinbefore described.), or by amidation or esterification of acompound of formula (IV)

[0297] (wherein E² is —COOH, —NHR⁹ or —OH, and the other symbols are thesame meanings as hereinbefore described.)

[0298] with a compound of formula (V)

E³—R³⁻¹  (V)

[0299] (wherein E³ is —OH, —NHR⁹ or —COOH, and the other symbol is thesame meaning as hereinbefore described.).

[0300] The above amidation is known per se and can be carried out by,for example:

[0301] (1) using an acid haride,

[0302] (2) using a mixed acid anhydride,

[0303] (3) using a condensing agent etc.

[0304] Each of those methods can be carried out, for example, asfollows:

[0305] (1) the method using an acid halide may be carried out, forexample, by reacting a carboxylic acid with an acid halide (e.g., oxalylchloride, thionyl chloride etc.) in an organic solvent (e.g.,chloroform, methylene chloride, diethyl ether, tetrahydrofuran, ethylacetate etc.) or without a solvent at from −20° C. to the refluxtemperature, and then by reacting the acid halide obtained with an aminein the presence of a tertiary amine (e.g., pyridine, triethylamine,dimethylaniline, dimethylaminopyridine, N-methylmorpholine etc.) in anorganic solvent (e.g., chloroform, methylene chloride, diethyl ether,tetrahydrofuran etc.) at 0° C.˜40° C.,

[0306] (2) the method using a mixed acid anhydride may be carried out,for example, by reacting a carboxylic acid and an acid halide (e.g.,pivaloyl chloride, tosyl chloride, mesyl chloride, ethyl chloroformate,isobutyl chloroformate etc.) in the presence of a tertiary amine (e.g.,pyridine, triethylamine, dimethylaniline, dimethylaminopyridine,N-methylmorpholine etc.) in an organic solvent (e.g., chloroform,methylene chloride, diethyl ether, tetrahydrofuran etc.) or without asolvent at −20° C.˜40° C., and then by reacting the mixture of acidanhydride obtained with a corresponding amine in an organic solvent(e.g., chloroform, methylene chloride, diethyl ether, tetrahydrofuranetc.), at 0° C.˜40° C.,

[0307] (3) the method using a condensing agent (e.g.,1,3-dicyclohexylcarbodiimide (DCC),1-ethyl-3-[3-(dimethylamino)propyl]cabodiimide (EDC),2-chlorolmethylpyridinium iodide, 1,1′-carbonyldiimidazole (CDI) etc.)may be carried out, for example, by reacting a carboxylic acid with anamine using a condensing agent in the presence or absence of a tertiaryamine (e.g., pyridine, triethylamine, dimethylaniline,dimethylaminopyridine etc.), in the presence or absence of1-hydroxybenzotriazole (HOBt) in an organic solvent (e.g., chloroform,methylene chloride, dimethyl formamide, diethyl ether, tetrahydrofuranetc.) or without a solvent at 0° C.˜40° C.

[0308] The reactions (1), (2) and (3) hereinbefore described may bepreferably carried out in an atmosphere of inert gas (e.g., argon,nitrogen etc.) under anhydrous conditions.

[0309] The above esterification is known per se and can be carried outby, for example:

[0310] (1) using an acid haride,

[0311] (2) using a mixed acid anhydride,

[0312] (3) using a condensing agent etc.

[0313] Each of those methods can be carried out, for example, asfollows:

[0314] (1) the method using an acid halide may be carried out, forexample, by reacting a carboxylic acid with an acid halide (e.g., oxalylchloride, thionyl chloride etc.) in an organic solvent (e.g.,chloroform, methylene chloride, diethyl ether, tetrahydrofuran ethylacetate etc.) or without a solvent at from −20° C. to the refluxtemperature, and then by reacting the acid halide obtained with analcohol in the presence of a tertiary amine (e.g., pyridine,triethylamine, dimethylaniline, dimethylaminopyridine,N-methylmorpholine etc.) in an organic solvent (e.g., chloroform,methylene chloride, diethyl ether, tetrahydrofuran etc.) at 0° C.˜40°C.,

[0315] (2) the method using a mixed acid anhydride may be carried out,for example, by reacting a carboxylic acid and an acid halide (e.g.,pivaloyl chloride, tosyl chloride, mesyl chloride, ethyl chloroformate,isobutyl chloroformate etc.) in the presence of a tertiary amine (e.g.,pyridine, triethylamine, dimethylaniline, dimethylaminopyridine,N-methylmorpholine etc.) in an organic solvent (e.g., chloroform,methylene chloride, diethyl ether, tetrahydrofuran etc.) or without asolvent at −20° C.˜40° C., and then by reacting the mixture of acidanhydride obtained with a corresponding alcohol in an organic solvent(e.g., chloroform, methylene chloride, diethyl ether, tetrahydrofuranetc.), at 0° C.˜40° C.,

[0316] (3) the method using a condensing agent (e.g.,1,3-dicyclohexylcarbodiimide (DCC),1-ethyl-3-[3-(dimethylamino)propyl]cabodiimide (EDC),2-chloro-1-methylpyridinium iodide, 1,1′-carbonyldiimidazole (CDI) etc.)may be carried out, for example, by reacting a carboxylic acid with analcohol using a condensing agent in the presence or absence of atertiary amine (e.g., pyridine, triethylamine, dimethylaniline,dimethylaminopyridine etc.), in the presence or absence of1-hydroxybenzotriazole (HOBt) in an organic solvent (e.g., chloroform,methylene chloride, dimethyl formamide, diethyl ether, tetrahydrofuranetc.) or without a solvent at 0° C.˜40° C.

[0317] The reactions (1), (2) and (3) hereinbefore described may bepreferably carried out in an atmosphere of inert gas (e.g., argon,nitrogen etc.) under anhydrous conditions.

[0318] Also, for the compounds of the formula (I-A), those in which E is—S—, i.e., the compounds of the formula (I-A-1)

[0319] (wherein all the symbols are the same meanings as hereinbeforedescribed.) may be prepared by the reaction of a compound of formula(VI)

[0320] (wherein X is halogen, and the other symbols is the same meaningas hereinbefore described.).

[0321] The reaction of a compound of formula (VI) with a compound offormula (VII) is known per se and can be carried out, for example, in anorganic solvent (e.g., dimethylformamide, acetone etc.), in the presenceof base (e.g., potassium carbonate etc.), at 0° C.˜40° C.

[0322] (b) For the compounds of the formula (i), those in which E is—SO—, —SO₂—, i.e., the compounds of formula (I-B)

[0323] (wherein E⁴ is —SO— or —SO₂— and the other symbols are the samemeanings as hereinbefore described.) may be prepared by the oxidation ofa compounds of formula (I-A) wherein E¹ is —S—.

[0324] The above oxidation is known per se, and in case of the oxidationfrom sulfide group to sulfoxide group, for example, it can be carriedout in an organic solvent (e.g., methylene chloride, chloroform,benzene, hexane, t-butyl alcohol etc.), in the presence of 1 equivalentof oxidizing agent (e.g., hydrogen peroxide, sodium periodate, acylnitrite, sodium perborate, peracid (e.g., m-chloroperbenzoic acid,peracetic acid etc.) etc.), in a few minutes, at −78° C. to

[0325] Also, in the case of the oxidation from sulfide group to sulfonegroup, for example, it can be carried out in an organic solvent (e.g.,methylene chloride, chloroform, benzene, hexane, t-butyl alcohol etc.),in the presence of an excess amount of oxidizing agent (e.g., hydrogenperoxide, sodium periodate, potassium pemanganate, sodium perborate,potassium hydrogen peroxosulfate, peracid (e.g., m-chloroperbenzoicacid, pracetic acid etc.) etc.), in a few hours, at −78° C.˜40° C.

[0326] (c) For the compounds of the formula (I), those in which E is—NR¹⁰—, i.e., the compounds of the formula (I-C)

[0327] (wherein all the symbols are the same meanings as hereinbeforedescribed.) may be prepared by the reaction of a compound of formula(VIII)

[0328] (wherein all the symbols are the same meanings as hereinbeforedescribed.) with a compound of formula (IX)

NHR¹⁰—R³⁻¹  (IX)

[0329] (wherein all the symbols are the same meanings as hereinbeforedescribed.).

[0330] The reaction of a compound of formula (VIII) with a compound offormula (IX) is known per se, and may be carried out, for example, in anorganic solvent (e.g., methanol, ethanol etc.), using reducing agent(e.g., sodium cyanoborohydride, sodium borohydride etc.), in thepresence or absence of pH modulator (e.g., acetic acid etc.), at 0°C.˜40° C.

[0331] (d) For the compounds of the formula (I), those in which E is—SO₂NR¹¹—, i.e., the compounds of the formula (I-D)

[0332] (wherein all the symbols are the same meanings as hereinbeforedescribed.) may be prepared by the reaction of a compound of formula (X)

[0333] (wherein all the symbols are the same meanings hereinbeforedescribed.) with a compound of formula (XI)

NHR¹¹—R³⁻¹  (XI)

[0334] (wherein all the symbols are the same meanings as hereinbeforedescribed.).

[0335] The reaction of a compound of formula (X) with a compound offormula (XI) is known per se, and may be carried out, for example, byreacting a compound of formula (X) with an acid halide (e.g., oxalylchloride, thionyl chloride, sulfulyl chloride etc.) in an organicsolvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuranetc.) in the presence of base (e.g., triphenylphosphine etc.) at −20° C.to the reflux temperature, and then by reacting the compound thusobtained with a compound of formula (XI) in the presence of a tertiaryamine (e.g., pyridine, triethylamine, diethylaniline,diethylaminopyridine etc.), in an organic solvent (e.g., chloroform,methylene chloride, diethyl ether, tetrahydrofuran etc.), at 0° C.˜40°C.

[0336] (e) For the compounds of the formula (I), those in which E is—NR¹²SO₂—, i.e., the compounds of the formula (I-E)

[0337] (wherein all the symbols are the same meanings as hereinbeforedescribed.) may be prepared by the reaction of a compound of formula(XII)

[0338] (wherein all the symbols are the same meanings as hereinbeforedescribed.) with a compound of formula (XIII)

X—SO₂—R³⁻¹  (XIII)

[0339] (wherein X is halogen, and the other symbol is the same meaningas hereinbefore described.).

[0340] The reaction of a compound of formula (XII) with a compound offormula (XIII) may be carried out, for example, in organic solvent(e.g., chloroform, methylene chloride, diethyl ether, tetrahydrofuranetc.), in the presence of a tertiary amine (e.g., pyridine,triethylamine, dimethylaniline, dimethylaminopyridine etc.), at 0°C.˜40° C.

[0341] (f) For the compounds of the formula (I), those in which A is—CO— or —SO₂—, i.e., the compounds of the formula (I-F)

[0342] (wherein A¹ is —CO— or —SO₂— and the other symbols are the samemeanings as hereinbefore described.)

[0343] may be prepared by amidation or sulfonamidation of a compound offormula (XIV)

[0344] (wherein all the symbols are the same meanings as hereinbeforedescribed.) with a compound of formula (XV)

R¹⁻¹—A²  (2)

[0345] (wherein A² is —COOH or —SO₃H, and the other symbol is the samemeaning as hereinbefore described.).

[0346] Sulfonamidation is known per se, and can be carried out, forexample, by reacting a sulfonic acid with an acid halide (e.g., oxalylchloride, thionyl chloride, phosphorus pentachloride, phosphorustrichloride etc.) in an inert organic solvent (e.g., chloroform,methylene chloride, diethyl ether, tetrahydrofuran etc.) or without asolvent at −20° C. to the reflux temperature, and then by reacting thesulfonyl halide obtained with a tertiary amine (e.g., pyridine,triethylamine, dimethylaniline, dimethylaminopyridine etc.) in an inertorganic solvent (e.g., chloroform, methylene chloride, diethyl ether,tetrahydrofuran etc.) at 0° C.˜40° C.

[0347] Also, amidation may be carried out by the same method ashereinbefore described.

[0348] (g) For the compounds of the formula (I), those in which A isbond, R¹ is C1-4 alkyl substituted by phenyl, C3-8 cycloalkyl, or heteroring, i.e., the compounds of the formula (I-G)

[0349] (wherein R¹² is C1-4 alkyl substituted by phenyl, C3-8cycloalkyl, or hetero ring (when amino group exists as a substituent ofeach ring, it may be protected, if necessary.), and the other symbolsare the same meanings as hereinbefore described.)

[0350] may be prepared by the reaction of a compound of formula (XIV)

[0351] (wherein all the symbols are the same meanings as hereinbeforedescribed.) with a compound of formula (XVI)

R¹⁻³—CHO  (XVI)

[0352] (wherein R¹⁻³ is phenyl, C3-8 cycloalkyl, hetero ring, or C1-3alkyl substituted by phenyl, C3-8 cycloalkyl or hetero ring (when aminogroup exists as a substituent of each ring, it may be protected, ifnecessary.)).

[0353] This reaction can be carried out by the same method in thereaction of a compound of formula (VIII) with a compound of formula(IX), as hereinbefore described.

[0354] (h) For the compounds of the formula (I), those in which R¹ ishetero ring, or C1-4 alkyl substituted by hetero ring, and a substituentof such a hetero ring is C2-5 acyl or C1-4 alkoxycarbonyl, i.e., thecompounds of the formula (I-H)

[0355] (wherein R²³ is bond or C1-4 alkylene, R²⁴ is C1-4 alkoxycarbonylor C2-5 acyl, R²⁵ is C1-4 alkyl, C1-4 alkoxy, phenyl, phenoxy,benzyloxy, —SR⁵, halogen, nitro or —NR⁶R⁷, n is 0˜2,

[0356] is the same meaning as hereinbefore described for hetero ring inR¹, provided that it contains at least one nitrogen atom. Also, whenamino group exists in a substituent represented by R²⁵, it may beprotected, if necessary, and the other symbols are the same meanings ashereinbefore described.) may be prepared by the amidation of a compoundof formula (XVII)

[0357] (wherein all the symbols are the same meanings as hereinbeforedescribed.) with a compound of formula (XVIII)

R²⁴—OH  (XVIII)

[0358] (wherein R²⁴ is the same meaning as hereinbefore described.)

[0359] The amidation can be carried out by the same method ashereinbefore described.

[0360] (i) In the compounds of the formula (I), the compounds of formula(I-I)

[0361] (wherein R¹⁻⁴, R³⁻² and R⁴⁻² are the same meanings ashereinbefore described for R¹, R³, R⁴, respectively, provided that atleast one of R¹⁻⁴, R³⁻² and R¹⁻² is a group containing —COOH, hydroxy oramino group, and the other symbols are the same meanings as hereinbeforedescribed.)

[0362] may be prepared by the deprotection under alkaline conditions,the deprotection under acidic conditions and/or hydrogenolysis of theabove compound of formulae (I-A), (I-A-1), (I-B), (I-C), (I-D), (I-E),(I-F), (I-G) or (I-H).

[0363] The deprotection under alkaline conditions is known per se, andmay be carried out, for example, in an organic solvent (e.g., methanol,tetrahydrofuran, dioxane etc.), using an alkali metal hydroxide (e.g.,sodium hydroxide, potassium hydroxide, lithium hydroxide etc.), analkaline earth metal hydroxide (e.g., calcium hydroxide etc.) or acarbonate (e.g., sodium carbonate, potassium carbonate etc.), an aqueoussolution thereof or a mixture thereof at 0° C.˜40° C.

[0364] The deprotection under acidic conditions is known per se, and maybe carried out, for example, in an organic solvent (e.g., methylenechloride, chloroform, dioxane, ethyl acetate, anisole etc.) or without asolvent, using an organic acid (e.g., trifluoroacetic acid,methanesulfonic acid, trimethylsilyl iodide etc.), or an inorganic acid(e.g., hydrogen chloride etc.) or a mixture thereof (e.ghydrobromoacetic acid etc.) at 0° C.˜90° C.

[0365] The hydrogenolysis is known per se, and may be carried out, forexample, in an organic solvent (e.g., tetrahydrofuran, dioxane, diethylether, ethyl acetate, methanol, ethanol etc.), in the presence of acatalyst (e.g., palladium carbon, palladium, palladium hydroxide,palladium acetate, palladium black, platinum black, nickel, Raney-nickeletc.), at ordinary or elevated pressure under an atmosphere hydrogengas, at 0° C.˜80° C.

[0366] It should be easily understood by those skilled in the art thatthe carboxy or hydroxy protecting group are not only t-butyl group orbenzyl group but any group which can be easily and selectivelyeliminated can be used in the present invention. For example, aprotecting group described in Protective Groups in Organic Synthesis (T.W. Greene, Wiley, New York (1991)) may be used. The amino protectinggroup are not only benzyloxycarbonyl group or t-butoxycarbonyl group butany group which can be easily and selectively eliminated can be used inthe present invention. The proposed compounds of the present inventionmay be easily prepared using those protecting groups.

[0367] The compounds of formulae (II), (III), (IV), (V), (VI), (VII),(VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII) or(XVIII) are known per se or may be prepared by methods known per se ormethods described in Example, but do not limit the present invention.

[0368] For example, the compounds of formula (X) may be prepared by themethods described in Liebigs Ann. Chem, 776-783, 1979.

[0369] For example, the compounds of formula (XII) may be prepared bythe methods described in J. Org. Chem, Vol. 44, No. 10, 1979.

[0370] For example, for the compounds of formula (XIV), those in which Eis —O—, —S—, —SO—, —SO₂—, i.e., the compound of formula (XIV′), and forthe compounds of formula (XVII), those in which E is —O—, —S—, —SO—,—SO₂— i.e., the compounds of formula (XVII′) may be prepared by themethod described in the following Scheme 1 and Scheme 2.

[0371] (in each Scheme, E⁵ is —O—, —S—, —SO—, or —SO₂—, Boc ist-butoxycarbonyl, (Boc)₂O is di-t-butyldicarbonate, R²⁶ is bond or C1-3alkylene, and the other symbols are the same meanings as hereinbeforedescribed.)

[0372] The reactions described in the above-mentioned Schemes may becarried out by known methods. In the above-mentioned Schemes, compoundsused for starting materials are may be known per se or may be easilyprepared by known methods.

[0373] In the present invention, the other starting materials and eachreagent are known per se or may be prepared by known methods.

[0374] In each reaction in the present specification, products may bepurified by a conventional manner. For example, it may be carried out bydistillation at atmospheric or reduced pressure, high performance liquidchromatography, thin layer chromatography or column chromatography usingsilica gel or magnesium silicate, washing or recrystallization.Purification may be carried out after each reaction, or after a seriesof reactions.

[0375] [Pharmacological Activity]

[0376] It has been confirmed that the compounds of the present inventionof the formula (I) possess an inhibitory action on N-type calciumchannel according to the following experiment.

[0377] Determination of Inhibitory Activity on N-Type Calcium Channel:

[0378] Cell line was differentiated according to the method described inFEBS Letters, 235, 178-182, 1988. The cell was loaded with fluorescentreagent, Fura-2•AM (at the final concentration of 10 μM), at 37° C. for30 minutes and suspended in Krebs-buffer containing HEPES (25 mM) toobtain the cell suspension. The obtained cell suspension was incubatedin the presence or absence of the compounds of the present inventionwith nifedipine for 5 minutes. The cell was depolarized by addingpotassium chloride solution (at the final concentration of 80 mM)thereto and then a fluorescence intensity at the emission wavelength of500 nm excited by the UV of 340 nm and 380 nm alternately was measuredusing the intracellular calcium analyzer (Nippon Bunko Co., CAF-110).The inhibitory activity of the compound of the present invention (at thefinal concentration of 3 μM) on calcium influx into the cell wascalculated from the difference in changing the fluorescence intensity atpeak (ΔR) according to the following equation. $\begin{matrix}{{Inhibitory}\quad {activity}\quad {of}\quad {the}\quad {compound}} \\{{of}\quad {the}\quad {present}\quad {{invention}{\quad \quad}( {3\mu \quad M} )}} \\{{on}\quad {calcium}\quad {inlux}\quad (\%)}\end{matrix} = {( {1 - \frac{\begin{matrix}{{Mean}\quad {of}\quad \Delta \quad R\quad {in}\quad {case}\quad {of}\quad {solution}} \\{{in}\quad {the}\quad {presence}\quad {of}\quad {the}\quad {compound}} \\{{of}\quad {the}\quad {present}\quad {invention}}\end{matrix}}{\begin{matrix}{{Mean}\quad {of}\quad \Delta \quad R\quad {in}\quad {case}\quad {of}\quad {solution}} \\{{in}\quad {the}\quad {absence}\quad {of}\quad {the}\quad {compound}} \\{{of}\quad {the}\quad {present}\quad {invention}}\end{matrix}}} ) \times 100}$

[0379] The results were shown in Table 41. TABLE 41 Inhibitory activityExample No. on Ca influx (%) 2 75 2 (29) 75 2 (80) 87 2 (86) 83 6 (22)79 6 (27) 72 6 (44) 86 6 (68) 73 9 (13) 88

[0380] From the results of an experiment using the patch-clamp techniquedescribed in Pflüngers Archives, 391, 85-100, 1981, the compounds of thepresent invention at the concentration of 10 μM showed clearly aninhibitory action on flux of barium ion (calcium current) passed throughan N-type calcium channel. The cells used in this experiment had beenincubated according to the method described in FEBS Letters, 235,178-182, 1988.

[0381] [Toxicity]

[0382] The toxicity of the compounds of the present invention are verylow and therefore, it may be considered that the compounds of thepresent invention are safe for pharmaceutical use.

[0383] [Application for Pharmaceuticals]

[0384] The compounds of the formula (I) possess an inhibitory action onN-type calcium channel, so they are useful as agent for the preventionand/or treatment of cerebral infarct, transient ischemic attack,encephalomyelopathy after cardiac operation, spinal angiopathy,hypertension with stress, neurosis or epilepsy etc. or agent for thetreatment of pain (for example, acute pain, chronic pain, pain afteroperation, cancer pain, neuralgia, pain caused by infection etc.).

[0385] For the purpose above described, the compounds of the generalformula (I), of the present invention, non-toxic salts thereof, acidaddition salts thereof and hydrates thereof may be normally administeredsystematically or partially, usually by oral or parenteraladministration.

[0386] The doses to be administered are determined depending upon age,body weight, symptom, the desired therapeutic effect, the route ofadministration, and the duration of the treatment etc. In the humanadult, the doses per person per dose are generally between 1 mg and 1000mg, by oral administration, up to several times per day, and between 1mg and 100 mg, by parenteral administration (preferred into vein) up toseveral times per day, or continuous administration between 1 and 24hrs. per day into vein.

[0387] As mentioned above, the doses to be used depend upon variousconditions. Therefore, there are cases in which doses lower than orgreater than the ranges specified above may be used.

[0388] When administration of the compounds of the present invention, itis used as solid compositions, liquid compositions or other compositionsfor oral administration, as injections, liniments or suppositories etc.for parenteral administration.

[0389] Solid compositions for oral administration include compressedtablets, pills, capsules, dispersible powders, and granules.

[0390] Capsules contain hard capsules and soft capsules.

[0391] In such compositions, one or more of the active compound(s) is orare, admixed with at least one inert diluent such as lactose, mannitol,glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch,polyinylpyrrolidone, magnesium metasilicate aluminate. The compositionsmay also comprise, as is normal practice, additional substances otherthan inert diluents: e.g. lubricating agents such as magnesium stearate,disintegrating agents such as cellulose calcium glycolate, and assistingagents for dissolving such as glutamic acid, asparaginic acid. Thetablets or pills may, if desired, be coated with film of gastric orenteric material such as sugar, gelatin, hydroxypropyl cellulose orhydroxypropyl cellulose phthalate etc., or be coated with two or morefilms. And further, coating may include containment within capsules ofabsorbable materials such as gelatin.

[0392] Liquid compositions for oral administration includepharmaceutically-acceptable emulsions, solutions, syrups and elixirsetc. In such liquid compositions, one or more of the active compound(s)is or are comprised in inert diluent(s) commonly used in the art (forexample, purified water, ethanol etc.). Besides inert diluents, suchcompositions may also comprise adjuvants such as wetting agents,suspending agents, sweetening agents, flavouring agents, perfumingagents and preserving agents.

[0393] Other compositions for oral administration include spraycompositions which may be prepared by known methods and which compriseone or more of the active compound(s). Spray compositions may compriseadditional substances other than inert diluents: e.g. stabilizing agentssuch as sodium hydrogen sulfate, stabilizing agents to give isotonicity,isotonic buffer such as sodium chloride, sodium citrate, citric acid.For preparation of such spray compositions, for example, the methoddescribed in the U.S. Pat. No. 2,868,691 or 3,095,355 may be used.

[0394] Injections for parenteral administration include sterile aqueousor non-aqueous solutions, suspensions and emulsions. Aqueous solutionsor suspensions include distilled water for injection and physiologicalsalt solution. Non-aqueous solutions or suspensions include propyleneglycol, polyethylene glycol, plant oil such as olive oil, alcohol suchas ethanol, POLYSOLBATE80 (registered trade mark) etc. Such compositionsmay comprise additional diluents: e.g. preserving agents, wettingagents, emulsifying agents, dispersing agents, stabilizing agent (forexample, lactose), assisting agents such as assisting agents fordissolving (for example, glutamic acid, asparaginic acid). They may besterilized for example, by filtration through a bacteria-retainingfilter, by incorporation of sterilizing agents in the compositions or byirradiation. They also may be manufactured in the form of sterile solidcompositions and which can be dissolved in sterile water or some othersterile diluents for injection immediately before used.

[0395] Other compositions for parenteral administration include liquidsfor external use, and endemic liniments, ointment, suppositories andpessaries which comprise one or more of the active compound(s) and maybe prepared by know methods.

REFERENCE EXAMPLE AND EXAMPLE

[0396] The following Reference Examples and Examples illustrate thepresent invention, but do not limit the present invention.

[0397] The solvents in the parentheses show the developing or elutingsolvents and the ratios of the solvents used are by volume inchromatographic separations and TLC.

[0398] NMR in the parentheses show measured solvents.

Reference Example 1(2S)-3-cyclohexylmethoxy-2-t-butoxycarbonylaminopropanoic acid

[0399]

[0400] Undercooling with ice, sodium hydride (60%, 3.95 g) was added toa solution of (2S)-3-hydroxy-2-t-butoxycarbonylaminopropanoic acid(10.11 g) in dimethylformamide (200 ml, hereinafter abbreviated as DMF).The mixture was stirred for 30 minutes at 0° C. Under cooling with ice,(bromomethyl)cyclohexane (9.0 ml) was added dropwise to the reactionmixture and tetrabutylammonium iodide (910 mg) was added thereto. Themixture was stirred for 23 hours at room temperature. Further,(bromomethyl)cyclohexane (2.1 ml) was added dropwise to the reactionmixture. The mixture was stirred for 4 hours. (Bromomethyl)cyclohexane(2.1 ml) was added dropwise to reaciton mixture again. The mixture wasstirred for 25 hours at room temperature. The reaction mixture wasconcentrated and the residue was diluted with 1N hydrochloric acid andextracted with ethyl acetate. The extract was washed with water andsaturated aqueous sodium chloride, successively, dried over anhydrousmagnesium sulfate. The organic layer was concentrated and the residuewas purified by silica gel column chromatography(chloroform:methanol=97:3) to give the title compound (2.52 g) havingthe following physical data.

[0401] TLC: Rf 0.21 (chloroform:methanol=9:1);

[0402] NMR (CDCl₃): δ 5.59-5.40 (1H, m), 4.46-4.27 (1H, m), 3.89-3.76(1H, m), 3.64 (1H, dd, J=9.4, 4.6 Hz), 3.27 (2H, d, J=6.2 Hz), 1.79-0.79(20H, m).

Reference Example 2(2R)-3-cyclohexylmethylthio-2-t-butoxycarbonylaminopropanoic acid

[0403]

[0404] To a solution of L-cysteine (133 mg) in ethanol (10 ml), 2Naqueous solution of sodium hydroxide (1.1 ml) and(bromomethyl)cyclohexane (0.17 ml) were added. The mixture was stirredfor 2.5 hours at room temperature. Two normal aqueous solution of sodiumhydroxide (0.6 ml) and di-tert-butyl dicarbonate (0.28 ml) were added tothe reaction mixture. The mixture was stirred for 1 hour. Ethanol wasremoved by evaporation from the reaction mixture and it was acidified byadding 1 N hydrochloric acid and extraced with ethyl acetate. Theextract was washed with saturated aqueous sodium chloride, dried overanhydrous magnesium sulfate. The organic layer was concentrated and theresidue was purified by silica gel column chromatography(chloroform:methanol=19:1) to give the title compound (135 mg) havingthe following physical data.

[0405] TLC: Rf 0.21 (ethyl acetate: acetic acid:water=9:1:1);

[0406] NMR (CDCl₃): δ 4.42-4.28 (1H, m), 3.01 (1H, dd, J=14.2, 5.2 Hz),2.92 (1H, dd, J=14.2, 3.4 Hz), 2.45 (2H, d, J=7.0 Hz), 1.91-0.81 (20H,m).

Example 1 (2S)-3-cycolpentyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.benzyl ester

[0407]

[0408] To a solution of(3S)-3-benzyloxycarbonyl-3-t-butoxycarbonylaminopropanoic acid (3.22 g),cyclopentanol (1.73 g) and dimethylaminopyridine (127 mg) in methylenechloride (20 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloric acid salt (3.83 g, hereinafter abbreviated as EDC-HCl) wasadded. The mixture was stirred for 2 hours at room temperature. Onenormal hydrochloric acid was added to the reaction mixture. The mixturewas extracted with methylene chloride. The extract was washed withsaturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate. The organic layer was concentrated and the residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=9:1) to givethe compound of the present invention (4.19 g) having thefollowingphysical data.

[0409] TLC: Rf 0.42 (hexane:ethyl acetate=4:1);

[0410] NMR (CDCl₃): δ 7.34 (5H, s), 5.50 (1H, d, J=8.3 Hz), 5.25-5.11(3H, m), 4.64-4.56 (1H, m), 2.97 (1H, dd, J=5.1, 16.9 Hz), 2.77 (1H, dd,J=4.8, 16.9 Hz), 1.88-1.54 (8H, m), 1.43 (9H, s).

Example 1(1)˜Example 1(20)

[0411] By the reaction of the corresponding carboxylic acid derivativeswith the corresponding alcohol derivatives or amine derivatives by thesame desired procedure as Example 1, the following compounds of thepresent invention were obtained.

Example 1(1) (2S)-3-benzyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.cyclohexyl ester

[0412]

[0413] TLC: Rf 0.45 (hexane:ethyl acetate=4:1);

[0414] 7.35 (5H, s), 5.50 (1H, d, J=7.5 Hz), 5.12 (2H, s), 4.86-4.73(1H, m), 4.58-4.49 (1H, m), 3.04 (1H, dd, J=4.5, 16.8 Hz), 2.86 (1H, dd,J=4.8, 16.8 Hz), 1.86-1.58 (4H, m), 1.55-1.18 (15H, m).

Example 1(2) (2S)-3-benzyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.cyclopentyl ester

[0415]

[0416] TLC: Rf 0.42 (hexane:ethyl acetate=4:1);

[0417] NMR (CDCl₃): δ 7.35 (5H, s), 5.97 (1H, d, J=7.8 Hz), 5.22-5.15(1H, m), 5.12 (2H, s), 4.56-4.47 (1H, m), 3.02 (1H, dd, J=4.8, 16.9 Hz),2.84 (1H, dd, J=4.8, 16.9 Hz), 1.88-1.49 (8H, m), 1.44 (9H, s).

Example 1(3) (2R)-3-benxyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.cyclohexyl ester

[0418]

[0419] TLC: Rf 0.45 (hexane:ethyl acetate=4:1);

[0420] 7.35 (5H, s), 5.50 (1H, d, J=7.5 Hz), 5.12 (2H, s), 4.86-4.73(1H, 4.58-4.49 (1H, m), 3.04 (1H, dd, J=4.5, 16.8 Hz), 2.86 (1H, dd,J=4.8, 16.8 Hz), 1.86-1.58 (4H, m), 1.55-1.18 (15H, m).

Example 1(4) (2R)-3-benzyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.cyclopentyl ester

[0421]

[0422] TLC: Rf 0.42 (hexane:ethyl acetate=4:1);

[0423] NMR (CDCl₃): δ 7.34 (5H, s), 5.51 (1H, d, J=7.6 Hz), 5.22-5.15(1H, m), 5.12 (2H, s), 4.57-4.47 (1H, m), 3.01 (1H, dd, J=4.8, 16.8 Hz),2.84 (1H, dd, J=4.8, 16.8 Hz), 1.86-1.50 (8H, m), 1.44 (9H, s).

Example 1(5)(2R)-3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.benzyl ester

[0424]

[0425] TLC: Rf 0.30 (hexane:ethyl acetate=6:1);

[0426] NMR (CDCl₃): δ 7.40-7.30 (5H, m), 5.50 (1H, bd, J=9.0 Hz), 5.20(1H, d, J=12 Hz), 5.18 (1H, d, J=12 Hz), 5.20-5.07 (1H, m), 4.65-4.50(1H, m), 2.93 (1H, dd, J=18, 5 Hz), 2.78 (1H, dd, J=18, 5 Hz), 1.80-1.48(8H, m), 1.44 (9H, s).

Example 1(6)(2S)-4-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminobutanoicacid.benzyl ester

[0427]

[0428] TLC: Rf 0.26 (hexane:ethyl acetate=5:1);

[0429] NMR (CDCl₃): δ 7.40-7.30 (5H, m), 5.24-5.08 (4H, m), 4.43-4.25(1H, m), 2.40-1.50 (12H, m), 1.43 (9H, s).

Example 1(7)(2R)-4-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminobutanoic acid.benzylEster

[0430]

[0431] TLC: Rf 0.46 (hexane:ethyl acetate=4:1);

[0432] NMR (CDCl₃): δ 7.35 (5H, s), 5.20 (1H, d, J=2.4 Hz), 5.13 (1H, d,J=9.2 Hz), 4.79-4.67 (1H, m), 4.41-4.31 (1H, m), 2.44-2.30 (2H, m),2.24-2.08 (1H, m), 2.04-1.66 (5H, m), 1.61-1.25 (15H, m).

Example 1(8)(2R)-4-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminobutanoicacid.benzyl ester

[0433]

[0434] TLC: Rf 0.42 (hexane:ethyl acetate=4:1);

[0435] NMR (CDCl₃): δ 7.35 (5H, s), 5.23-5.08 (4H, m), 4.40-4.29 (1H,m), 2.43-2.28 (2H, m), 2.23-2.03 (1H, m), 2.02-1.49 (9H, m), 1.42 (9H,s).

Example 1(9) (2S)-4-benzyloxycarbonyl-2-t-butoxycarbonylaminobutanoicacid.cyclohexyl ester

[0436]

[0437] TLC: Rf 0.51 (hexane:ethyl acetate=4:1);

[0438] NMR (CDCl₃): δ 7.34 (5H, s), 5.18-5.04 (3H, m), 4.85-4.74 (1H,m), 4.37-4.24 (1H, m), 2.59-1.25 (23H, m).

Example 1 (10) (2S)-4-benzyloxycarbonyl-2-t-butoxycarbonylaminobutanoicacid.cyclopentyl ester

[0439]

[0440] TLC: Rf 0.50 (hexane:ethyl acetate=4:1);

[0441] NMR (CDCl₃): δ 7.36 (5H, s), 5.25-5.11 (4H, m), 4.37-4.15 (1H,m), 2.58-1.34 (21H, m).

Example 1(11) (2R)-4-benzyloxycarbonyl-2-t-butoxycarbonylaminobutanoicacid.cyclohexyl ester

[0442]

[0443] TLC: Rf 0.51 (hexane:ethyl acetate=4:1);

[0444] NMR (CDCl₃): δ 7.36 (5H, s), 5.13 (2H, s), 5.14-5.04 (1H, m),4.88-4.73 (1H, m), 4.39-4.22 (1H, m), 2.58-1.24 (23H, m).

Example 1(12) (2R)-4-benzyloxycarbonyl-2-t-butoxycarbonylaminobutanoicacid.cyclopentyl ester

[0445]

[0446] NMR (CDCl₃): δ 7.35 (5H, s), 5.25-5.03 (4H, m), 4.37-4.13 (1H,m), 2.59-1.37 (21H, m).

Example 11(13)(2S)-3-cyclohexylcarbomoyl-2-t-butoxycarbonylaminopropanoic acid.benzylester

[0447]

[0448] TLC: Rf 0.29 (hexane:ethyl acetate=2:1);

[0449] NMR (CDCl₃): δ 7.43-7.25 (5H, m), 5.81 (1H, bd, J=9 Hz), 5.50(1H, bd, J=9 Hz), 5.21 (1H, d, J=10 Hz), 5.16 (1H, d, J=10 Hz),4.59-4.46 (1H, m), 3.81-3.60 (1H, m), 2.83 (1H, dd, J=16, 5 Hz), 2.68(1H, dd, J=16, 5 Hz), 1.95-0.94 (10H, m), 1.42 (9H, s).

Example 1(14)(2S)-3-cyclopentylcarbamoyl-2-t-butoxycarbonylaminopropanoic acid.benzylester

[0450]

[0451] TLC: Rf 0.26 (hexane:ethyl acetate=2:1);

[0452] NMR (CDCl₃): δ 7.43-7.25 (5H, m), 5.90-5.74 (1H, m), 5.73-5.55(1H, m), 5.21 (1H, d, J=12 Hz), 5.16 (1H, d, J=12 Hz), 4.60-4.46 (1H,m), 4.24-4.05 (1H, m), 2.82 (1H, dd, J=16, 5 Hz), 2.68 (1H, dd, J=16, 5Hz), 2.08-1.19 (8H, m), 1.42 (9H, s).

Example 1 (15)(2S)-4-(pyrrolidin-1-ylcarbonyl)-2-t-butoxycarbonylaminobutanoicacid.benzyl ester

[0453]

[0454] TLC: Rf 0.33 (hexane:ethyl acetate=1:1);

[0455] NMR (CDCl₃): δ 7.40-7.30 (5H, m), 5.60-5.45 (1H, m), 5.21 (1H, d,J=12 Hz), 5.14 (1H, d, J=12 Hz), 4.40-4.23 (1H, m), 3.44 (2H, t, J=7Hz), 3.27 (2H, t, J=7 Hz), 2.37-1.65 (8H, m), 1.44 (9H, s).

Example 1(16)(2S)-3-cyclopentyloxycarbonyl-2-(N-t-butoxycarbonyl-N-methylamino)-propanoicacid.4-nitrobenzyl ester

[0456]

[0457] TLC: Rf 0.49 (ethyl acetate:hexane=1:2);

[0458] NMR (CDCl₃): δ 8.25-8.18 (2H, m), 7.51 (2H, d, J=8.8 Hz),5.30-5.11 (3H, m), 4.82-4.60 (1H, m), 3.17-2.66 (5H, m), 1.98-1.33 (17H,m).

Example 1 (17)(2S)-3-cyclohexyloxycarbonyl-2-(N-t-butoxycarbonyl-N-amino)propanoicacid.4-nitrobenzyl ester

[0459]

[0460] TLC: Rf 0.38 (ethyl acetate:hexane=1:2);

[0461] NMR (CDCl₃): δ 8.28-8.15 (2H, m), 7.51 (2H, d, J=8.8 Hz),5.38-5.14 (2H, m), 4.85-4.62 (2H, m), 3.18-3.01 (1H, m), 2.98-2.69 (4H,m), 1.94-1.16 (19H, m).

Example 1(18)(2S)-3-cuyclobutyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.benzyl ester

[0462]

[0463] TLC: Rf 0.59 (hexane:ethyl acetate=2:1);

[0464] NMR (CDCl₃): δ 7.36-7.31 (5H, m), 5.50 (1H, d, J=8.0 Hz), 5.22(1H, d, J=12.4 Hz), 5.14 (1H, d, J=12.4 Hz), 5.01-4.86 (1H, m),4.65-4.56 (1H, m), 2.99 (1H, dd, J=16.4, 6.0 Hz), 2.78 (1H, dd, J=16.4,4.8 Hz), 2.39-2.21 (2H, m), 2.12-1.50 (4H, m), 1.43 (9H, s).

Example 1(19)(2S)-3-(adamantan-2-yloxycarbonyl)-2-t-butoxycarbonylaminopropanoicacid.benzyl ester

[0465]

[0466] TLC: Rf 0.46 (hexane:ethyl acetate=4:1);

[0467] NMR (CDCl₃): δ 7.34 (5H, s), 5.54 (1H, d, J=8.8 Hz), 5.22 (1H, d,J=12.2 Hz), 5.13 (1H, d, J=12.2 Hz), 4.93-4.87 (1H, br), 4.66-4.57 (1H,m), 3.04 (1H, dd, J=4.4, 16.8 Hz), 2.85 (1H, dd, J=4.6, 16.8 Hz),2.01-1.65 (12H, m), 1.60-1.46 (2H, m), 1.43 (9H, s).

Example 1(20)(2S)-3(adamantan-1-yloxycarbonyl)-2-t-butoxycarbonylaminopropanoicacid.benzyl ester

[0468]

[0469] TLC: Rf 0.46 (hexane:ethyl acetate=4:1)

[0470] NMR (CDCl₃): δ 7.34 (5H, s), 5.50 (1H, d, J=8.6 Hz), 5.23 (1H, d,J=12.4 Hz), 5.13 (1H, d, J=12.4 Hz), 4.60-4.52 (1H, m), 2.93 (1H, dd,J=4.6, 16.8 Hz), 2.71 (1H, dd, J=4.8, 16.8 Hz), 2.19-2.08 (3H, br), 2.02(6H, d, J=3.0 Hz), 1.63 (6H, s), 1.44 (9H, s).

Reference Example 3(2S)-3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid

[0471]

[0472] Under argon atmosphere, the compound prepared in Example 1 (4.19g) was stirred in ethyl acetate (25 ml) and palladium carbon (5%, 500mg) was added thereto. The mixture was stirred for 13 hours at roomtemperature under hydrogen atmosphere. The reaction mixture was filteredthrough Celite. The filtrate was concentrated to give the title compound(2.98 g) having the following physical data.

[0473] TLC: Rf 0.53 (chloroform:methanol=9:1);

[0474] NMR (CDCl₃): δ 5.54 (1H, d, J=8.1 Hz), 5.24-5.17 (1H, m),4.63-4.55 (1H, m), 2.97 (1H, dd, J=4.8, 17.1 Hz), 2.79 (1H, dd, J=4.8,17.1 Hz), 1.87-1.55 (8H, m), 1.45 (9H, s).

Example 2(2S0-N-(4-methoxybenzyl)-3-cyclohexylmethoxy-2-t-butoxycarbonylamino-propanamide

[0475]

[0476] The compound prepared in Reference Example 1 (90 mg),dimethylaminopyridine (6 mg) and 4-methoxybenzylamine (43 mg) weredissolved in methylene chloride, and EDC-HCl (122 mg) was added thereto.The mixture was stirred for 12 hours at room temperature. The reactionmixture was concentrated. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=3:1) to give the compound of thepresent invention (84 mg) having the following physical data.

[0477] TLC: Rf 0.20 (hexane:ethyl acetate=3:1);

[0478] NMR (CDCl₃): δ 7.19 (2H, d, J=8.2 Hz), 6.85 (2H, d, J=8.2 Hz),6.80-6.66 (1H, br), 5.52-5.26 (1H, br), 4.44 (1H, dd, J=5.2, 15.0 Hz),4.36 (1H, dd, J=5.8, 15.0 Hz), 4.30-4.15 (1H, br), 3.89-3.79 (4H, m),3.44 (1H, dd, J=7.0, 9.2 Hz), 3.27 (1H, dd, J=6.1, 9.3 Hz), 3.20 (1H,dd, J=6.1, 9.3 Hz), 1.94 (5H, m), 1.44 (9H, s), 1.34-1.04 (4H, m),0.96-0.74 (2H, m).

Example 2(1)˜Example 2(119)

[0479] By the reaction of the compounds prepared in Reference Example 1,Reference Example 2, Reference Example 3, or the carboxylic acidderivatives (obtained by the same desired procedure as Reference Example3, using the compounds prepared in Example 1(1)˜Example 1(20)) or thecorresponding carboxylic acids derivatives thereof with thecorresponding alcohol derivatives or amine derivatives by the samedesired procedure as Example 2, the following compounds of the presentinvention were obtained.

Example 2(1)(2S)-4-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminobutanoicacid.4-nitrobenzyl ester

[0480]

[0481] TLC: Rf 0.37 (hexane:ethyl acetate=4:1);

[0482] NMR (CDCl₃): δ 8.23 (2H, d, J=8.8 Hz), 7.53 (2H, d, J=8.8 Hz),5.27 (2H, s), 5.12 (1H, d, J=8.6 Hz), 4.80-4.69 (1H, m), 4.44-4.33 (1H,m), 2.43-2.36 (2H, m), 2.31-1.20 (21H. m).

Example 2(2)(2S)-3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.4-fluorobenzyl ester

[0483]

[0484] TLC: Rf 0.36 (hexane:ethyl acetate=4:1);

[0485] NMR (CDCl₃): δ 7.36-7.29 (2H, m), 7.08-6.99 (2H, m), 5.48 (1H, d,J=2.3 Hz), 5.17 (1H, d, J=2.4 Hz), 5.09 (1H, d, J=12.4 Hz), 4.80-4.65(1H, m), 4.65-4.52 (1H, m), 2.99 (1H, dd, J=4.5, 16.8 Hz), 2.78 (1H, dd,J=4.8, 16.8 Hz), 1.87-1.47 (6H, m), 1.43 (9H, s), 1.40-1.20 (4H, m).

Example 2(3)(2R)-3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacic.4-fluorobenzyl ester

[0486]

[0487] TLC: Rf 0.46 (ethyl acetate:hexane=1:4);

[0488] NMR (CDCl₃): δ 7.36-7.29 (2H, m), 7.08-6.99 (2H, m), 5.49 (1H, d,J=8.5 Hz), 5.19 (1H, d, J=12.2 Hz), 5.09 (1H, d, J=12.2 Hz), 4.73-4.57(2H, m), 2.98 (1H, dd, J=16.8, 4.8 Hz), 2.78 (1H, dd, J=16.8, 4.7 Hz),1.80-1.24 (19H, m).

Example 2(4)(2S)-3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.4-methoxybenzyl ester

[0489]

[0490] TLC: Rf 0.39 (hexane:ethyl acetate=4:1);

[0491] NMR (CDCl₃): δ 7.27 (2H, d, J=8.6 Hz), 6.87 (2H, d, J=8.6 Hz),5.52-5.42 (1H, m), 5.15 (1H, d, J=12.0 Hz), 5.07 (1H, d, J=12.0 Hz),4.75-4.64 (1H, m), 4.62-4.50 (1H, m), 3.81 (3H, s), 2.98 (1H, dd, J=4.4,16.8 Hz), 2.76 (1H, dd, J=5.0, 16.8 Hz), 1.90-1.52 (6H, m), 1.43 (9H,s), 1.40-1.22 (4H, m).

Example 2(5)(2R)-3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.4-methoxybenzyl ester

[0492]

[0493] TLC: Rf 0.31 (ethyl acetate:hexane=1:4);

[0494] NMR (CDCl₃): δ 7.27 (2H, d, J=8.5 Hz), 6.87 (2H, d, J=8.5 Hz),5.48 (1H, d, J=10.4 Hz), 5.15 (1H, d, J=12.0 Hz), 5.07 (1H, d, J=12.0Hz), 4.73-4.55 (2H, m), 3.81 (3H, s), 2.98 (1H, dd, J=6.8, 4.8 Hz), 2.77(1H, dd, J=6.8, 4.6 Hz), 1.82-1.09 (19H, m).

Example 2(6)(2S)-3-cyclohexyloxycarbonyl-2-benzyloxycarbonylaminopropanoicacid.4-nitrobenzyl ester

[0495]

[0496] TLC: Rf 0.17 (ethyl acetate:hexane=1:4).

[0497] NMR (CDCl₃): δ 8.20 (2H, d, J=8.5 Hz), 7.48 (2H, d, J=8.5 Hz),7.35 (5H, s), 5.78 (1H, d, J=8.8 Hz), 5.33-5.19 (2H, m), 5.13 (2H, s),4.76-4.67 (2H, m), 3.06 (1H, dd, J=17.2, 4.4 Hz), 2.83 (1H, dd, J=17.2,4.4 Hz), 1.75-1.22 (10H, m).

Example 2(7)(2S)-3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.4-nitrophenethyl ester

[0498]

[0499] TLC: Rf 0.44 (hexane:ethyl acetate=3:1)

[0500] NMR (CDCl₃): δ 8.18 (2H, d, J=8.2 Hz), 7.39 (2H, d, J=8.2 Hz),5.43 (1H, d, J=9.6 Hz), 4.78-4.61 (1H, m), 4.60-4.46 (1H, m), 4.40 (2H,t, J=6.6 Hz), 3.07 (2H, t, J=6.6 Hz), 2.94 (1H, dd, J=4.8, 17.1 Hz),2.76 (1H, dd, J=4.6, 17.1 Hz), 1.88-1.48 (6H, m), 1.44 (9H, s),1.41-1.22 (4H, m).

Example 2(8)(2S)-N-benzyl-3-cyclohexyloxycarbonyl-2-t-butoxycarbonylamino-propanamide

[0501]

[0502] TLC: Rf 0.37 (hexane:ethyl acetate=3:1);

[0503] NMR (CDCl₃): δ 7.38-7.21 (5H, m), 6.88-6.72 (1H, br), 5.75-5.58(1H, m), 4.82-4.68 (1H, m), 4.58-4.38 (3H, m), 3.02 (1H, dd, J=4.6, 17.0Hz), 2.70 (1H, dd, J=6.4, 17.0 Hz), 1.91-1.47 (6H, m), 1.43 (9H, s),1.40-1.23 (4H, m).

Example 2(9)(2S)-3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.4-methoxybenzyl ester

[0504]

[0505] TLC: Rf 0.34 (hexane:ethyl acetate=4:1);

[0506] NMR (CDCl₃): δ 7.27 (2H, d, J=8.6 Hz), 6.88 (2H, d, J=8.6 Hz),5.48 (1H, d, J=8.8 Hz), 5.18-5.04 (3H, m), 4.60-4.51 (1H, m), 3.81 (3H,s), 2.96 (1H, dd, J=4.8, 17.0 Hz), 2.76 (1H, dd, J=4.8, 16.8 Hz),1,83-1.54 (8H, m), 1.43 (9H, s).

Example 2(10)(2S)-3-(4-methoxybenzyloxycarbonyl)-2-t-butoxycarbonylaminopropanoicacid.cyclohexyl ester

[0507]

[0508] TLC: Rf 0.39 (hexane:ethyl acetate=4:1);

[0509] NMR (CDCl₃): δ 7.28 (2H, d, J=8.6 Hz), 6.88 (2H, d, J=8.6 Hz),5.48 (1H, d, J=8.6 Hz), 5.05 (2H, s), 4.84-4.72 (1H, m), 4.57-4.47 (1H,m), 3.81 (3H, s), 3.02 (1H, dd, J=4.4, 16.8 Hz), 2.82 (1H, dd, J=4.8,16.8 Hz), 1.85-1.60 (4H, m), 1.56-1.27 (15H, m).

Example 2(11)(2S)-3-(4-nitrobenzyloxycarbonyl)-2-t-butoxycarbonylaminopropanoic acidcyclohexyl ester

[0510]

[0511] TLC: Rf 0.18 (hexane:ethyl acetate=4:1);

[0512] NMR (CDCl₃): δ 8.23 (2H, d, J=8.8 Hz), 7.52 (2H, d, J=8.8 Hz),5.48 (1H, d, J=8.0 Hz), 5.22 (2H, s), 4.86-4.74 (1H, m), 4.60-4.52 (1H,m), 3.07 (1H, dd, J=4.6, 16.8 Hz), 2.92 (1H, dd, J=5.0, 16.8 Hz),1.88-1.58 (4H, m), 1.56-1.20 (15H, m).

Example 2(12)(2S)-3-(4-methoxybenzyloxycarbonyl)-2-t-butoxycarbonylaminopropanoicacid cyclopentyl ester

[0513]

[0514] TLC: Rf 0.24 (hexane:ethyl acetate=4:1);

[0515] NMR (CDCl₃): δ 7.28 (2H, d, J=8.8 Hz), 6.88 (2H, d, J=8.8 Hz),5.47 (1H, d, J=8.4 Hz), 5.21-5.16 (1H, m), 5.05 (2H, s), 4.54-4.45 (1H,m), 3.81 (3H, s), 2.98 (1H, dd, J=4.8, 16.8 Hz), 2.76 (1H, dd, J=4.6,16.8 Hz), 1.88-1.51 (8H, m), 1.44 (9H, s).

Example 2(13)(2S)-3-(4-nitrobenzyloxycarbonyl)-2-t-butoxycarbonylaminopropanoic acidcyclopentyl ester

[0516]

[0517] TLC: Rf 0.15 (hexane:ethyl acetate=4:1);

[0518] NMR (CDCl₃): δ 8.23 (2H, d, J=8.8 Hz), 7.51 (2H, d, J=8.8 Hz),5.44 (1H, d, J=8.4 Hz), 5.22-5.17 (3H, m), 4.59-4.50 (1H, m), 3.04 (1H,dd, J=4.8, 16.8 Hz), 2.92 (1H, dd, J=5.0, 16.8 Hz), 1.94-1.52 (8H, m),1.44 (9H, s).

Example 2(14)(2R)-3-(4-methoxybenzyloxycarbonyl)-2-t-butoxycarbonylaminopropanoicacid.cyclohexyl ester

[0519]

[0520] TLC: Rf 0.39 (hexane:ethyl acetate=4:1);

[0521] NMR (CDCl₃): δ 7.28 (2H, d, J=8.6 Hz), 6.88 (2H, d, J=8.6 Hz),5.48 (1H, d, J=8.6 Hz), 5.05 (2H, s), 4.84-4.72 (1H, m), 4.57-4.47 (1H,m), 3.81 (3H, s), 3.02 (1H, dd, J=4.4, 16.8 Hz), 2.82 (1H, dd, J=4.8,16.8 Hz), 1.85-1.60 (4H, m), 1.56-1.27 (15H, m).

Example 2(15)(2R)-3-(4-nitrobenzyloxycarbonyl)-2-t-butoxycarbonylaminopropanoicacid.cyclohexyl ester

[0522]

[0523] TLC: Rf 0.18 (hexane:ethyl acetate=4:1);

[0524] NMR (CDCl₃): δ 8.23 (2H, d, J=8.8 Hz), 7.52 (2H, d, J=8.8 Hz),5.48 (1H, d, J=8.0 Hz), 5.22 (2H, s), 4.86-4.74 (1H, m), 4.60-4.52 (1H,m), 3.07 (1H, dd, J=4.6, 16.8 Hz), 2.92 (1H, dd, J=5.0, 16.8 Hz),1.88-1.58 (4H, m), 1.56-1.20 (15H, m).

Example 2(16)(2R)-3-(4-methoxybenzyloxycarbonyl)-2-t-butoxycarbonylaminopropanoicacid.cyclopentyl ester

[0525]

[0526] TLC: Rf 0.24 (hexane:ethyl acetate=4:1)

[0527] NMR (CDCl₃): δ 7.28 (2H, d, J=8.8 Hz), 6.88 (2H, d, J=8.8 Hz),5.47 (1H, d, J=8.4 Hz), 5.21-5.16 (1H, m), 5.05 (2H, s), 4.54-4.45 (1H,m), 3.81 (3H, s), 2.98 (1H, dd, J=4.8, 16.8 Hz), 2.76 (1H, dd, J=4.6,16.8 Hz), 1.88-1.51 (8H, m), 1.44 (9H, s).

Example 2(17)(2R)-3-(4-nitrobenzyloxycarbonyl)-2-t-butoxycarbonylaminopropanoicacid.cyclopentyl ester

[0528]

[0529] TLC: Rf 0.15(hexane:ethyl acetate=4:1)

[0530] NMR (CDCl₃): δ 8.23 (2H, d, J=8.8 Hz), 7.51 (2H, d, J=8.8 Hz),5.44 (1H, d, J=8.4 Hz), 5.22-5.17 (3H, m), 4.59-4.50 (1H, m), 3.04 (1H,dd, J=4.8, 16.8 Hz), 2.92 (1H, dd, J=5.0, 16.8 Hz), 1.94-1.52 (8H, m),1.44 (9H, s).

Example 2(18)(2R)-3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.4-methoxybenzyl ester

[0531]

[0532] TLC: Rf 0.20 (ethyl acetate:hexane=1:5);

[0533] NMR (CDCl₃): δ 7.27 (2H, d, J=9 Hz), 6.88 (2H, d, J=9 Hz), 5.48(1H, d, J=8 Hz), 5.20-5.03 (3H, m), 4.63-4.48 (1H, m), 3.81 (3H, s),2.93 (1H, dd, J=18, 5 Hz), 2.77 (1H, dd, J=18, 5 Hz), 1.90-1.48 (8H, m),1.43 (9H, s).

Example 2(19)(2S)-4-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminobutanoicacid.4-methoxybenzyl ester

[0534]

[0535] TLC: Rf 0.33 (ethyl acetate:hexane=1:4);

[0536] NMR (CDCl₃): δ 7.22 (2H, d, J=9 Hz), 6.81 (2H, d, J=9 Hz),5.12-4.95 (3H, m), 4.75-4.59 (1H, m), 4.33-4.15 (1H, m), 3.74 (3H, s),2.40-1.05 (14H, m), 1.35 (9H, s).

Example 2(20)(2S)-4-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminobutanoicacid.4-methoxybenzyl ester

[0537]

[0538] TLC: Rf 0.17 (ethyl acetate:hexane=1:5);

[0539] NMR (CDCl₃): δ 7.29 (2H, d, J=9 Hz), 6.88 (2H, d, J=9 Hz),5.20-5.03 (4H, m), 4.40-4.23 (1H, m), 3.81 (3H, s), 2.40-1.48 (12H, m),1.42 (9H, s).

Example 2(21)(2S)-4-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminobutanoicacid.4-nitrobenzyl ester

[0540]

[0541] TLC: Rf 0.16 (ethyl acetate:hexane=1:4);

[0542] NMR (CDCl₃): δ 8.23 (2H, d, J=9 Hz) 7.53 (2H, d, J=9 Hz), 5.27(2H, s), 5.21-5.05 (2H, m) 4.47-4.28 (1H, m) 2.46-1.49 (12H, m), 1.44(9H, s).

Example 2(22)(2R)-4-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminobutanoicacid.4-methoxybenzyl ester

[0543]

[0544] TLC: Rf 0.33 (hexane:ethyl acetate=4:1);

[0545] NMR (CDCl₃): δ 7.29 (2H, d, J=8.8 Hz), 6.88 (2H, d, J=8.8 Hz),5.17-5.04 (3H, m), 4.79-4.69 (1H, m), 4.39-4.25 (1H, m), 3.81 (3H, s),2.43-2.29 (2H, m), 2.24-2.05 (1H, m), 2.03-1.53 (7H, m), 1.51-1.27 (13H,m).

Example 2(23)(2R)-4-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminobutanoicacid.4-nitrobenzyl ester

[0546]

[0547] TLC: Rf 0.26 (hexane:ethyl acetate=4:1);

[0548] NMR (CDCl₃): δ 8.23 (2H, d, J=8.8 Hz), 7.53 (2H, d, J=8.8 Hz),5.29 (2H, s), 5.12 (1H, d, J=9.0 Hz), 4.81-4.69 (1H, m), 4.45-4.34 (1H,m), 2.48-2.35 (2H, m), 2.30-2.11 (1H, m), 2.07-1.53 (7H, m), 1.51-1.28(13H, m).

Example 2(24)(2R)-4-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminobutanoicacid.4-methoxybenzyl ester

[0549]

[0550] TLC: Rf 0.34 (hexane:ethyl acetate=4:1);

[0551] NMR (CDCl₃): δ 7.29 (2H, d, J=8.8 Hz), 6.88 (2H, d, J=8.8 Hz),5.19-5.04 (4H, m), 4.37-4.26 (1H, m), 3.81 (3H, S), 2.44-2.27 (2H, m),2.23-2.04 (1H, m), 2.00-1.57 (9H, m), 1.43 (9H, s).

Example 2(25)(2R)-4-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminobutanoicacid.4-nitrobenzyl ester

[0552]

[0553] TLC: Rf 0.21 (hexane:ethyl acetate=4:1);

[0554] NMR (CDCl₃): δ 8.23 (2H, d, J=8.8 Hz), 7.53 (2H, d, J=8.8 Hz),5.27 (2H, s), 5.20-5.09 (2H, m), 4.43-4.33 (1H, m), 2.50-2.33 (2H, m),2.28-2.10 (1H, m), 2.06-1.52 (9H, m), 1.43 (9H, s).

Example 2(26)(2S)-4-(4-methoxybenzyloxycarbonyl)-2-t-butoxycarbonylaminobutanoicacid.cyclohexyl ester

[0555]

[0556] TLC: Rf 0.29 (ethyl acetate:hexane=1:4);

[0557] NMR (CDCl₃): δ 7.34-7.20 (2H, m), 6.94-6.81 (2H, m), 5.12-5.00(1H, m), 5.05 (2H, s), 4.84-4.74 (1H, m), 4.36-4.20 (1H, m), 3.81 (3H,s), 2.47-1.22 (23H, m).

Example 2(27)(2S)-4-(4-nitrobenzyloxycarbonyl)-2-t-butoxycarbonylaminobutanoicacid.cyclohexyl ester

[0558]

[0559] TLC: Rf 0.27 (ethyl acetate:hexane=1:4);

[0560] NMR (CDCl₃): δ 8.29-8.18 (2H, m), 7.56-7.46 (2H m), 7.52 (2H, d,J=8.8 Hz), 5.30-5.05 (3H, m), 4.86-4.75 (1H, m), 4.37-4.25 (1H, m),2.64-2.38 (2H, m), 2.33-2.13 (1H, m), 2.06-1.17 (20H, m).

Example 2(28)(2S)-4-(4-methoxybenzyloxycarbonyl)-2-t-butoxycarbonylaminobutanoicacid.cyclopentyl ester

[0561]

[0562] TLC: Rf 0.29 (ethyl acetate:hexane=1:4);

[0563] NMR (CDCl₃): δ 7.28 (2H, d, J=11.2 Hz), 6.89 (2H, d, J=11.2 Hz),5.24-5.20 (1H, m), 5.13-5.01 (1H, m), 5.05 (2H, s), 4.31-4.21 (1H, m),3.81 (3H, s), 2.47-1.59 (12H, m), 1.43 (9H, s).

Example 2(29)(2S)-4-(4-nitrobenzyloxycarbonyl)-2-t-butoxycarbonylaminobutanoicacid.cyclopentyl ester

[0564]

[0565] TLC: Rf 0.20 (ethyl acetate:hexane=1:4);

[0566] NMR (CDCl₃): δ 8.28-8.18 (2H, m), 7.76-7.46 (2H, m), 5.25-5.06(2H, m), 5.22 (2H, s), 4.35-4.24 (1H, m), 2.55-2.47 (2H, m), 2.40-1.53(10H, m), 1.44 (9H, s).

Example 2(30)(2R)-4-(4-methoxybenzyloxycarbonyl)-2-t-butoxycarbonylaminobutanoicacid.cyclohexyl ester

[0567]

[0568] TLC: Rf 0.42 (ethyl acetate:hexane=1:4);

[0569] NMR (CDCl₃): δ 7.33-7.23 (2H, m), 6.93-6.84 (2H, m), 5.12-5.00(1H, m), 5.05 (2H, s), 4.84-4.74 (1H, m), 4.36-4.20 (1H, m), 3.81 (3H,s), 2.47-1.22 (23H, m).

Example 2(31)(2R)-4-(4-nitrobenzyloxycarbonyl)-2-t-butoxycarbonylaminobutanoicacid.cyclohexyl ester

[0570]

[0571] TLC: Rf 0.27 (ethyl acetate:hexane=1; 4);

[0572] NMR (CDCl₃): δ 8.26-8.18 (2H, m), 7.56-7.46 (2H, m), 5.22 (2H,s), 5.15-5.06 (1H, m), 4.86-4.75 (1H, m), 4.37-4.25 (1H, m), 2.56-1.20(23H, m).

Example 2(32)(2R)-4-(4-methoxybenzyloxycarbonyl)-2-t-butoxycarbonylaminobutanoicacid.cyclopentyl ester

[0573]

[0574] TLC: Rf 0.29 (ethyl acetate:hexane=1:4);

[0575] NMR (CDCl₃): δ 7.33-7.24 (2H, m), 7.28 (2H, d, J=11.2 Hz),6.93-6.84 (2H, m), 6.89 (2H, d, J=11.2 Hz), 5.24-5.03 (2H, m), 5.05 (2H,S), 4.31-4.21 (1H, m), 3.81 (3H, s), 2.47-1.59 (12H, m), 1.43 (9H, s).

Example 2(33)(2R)-4-(4-nitrobenzyloxycarbonyl)-2-t-butoxycarbonylaminobutanoicacid.cyclopentyl ester

[0576]

[0577] TLC: Rf 0.24 (ethyl acetate:hexane=1:4);

[0578] NMR (CDCl₃): δ 8.25-8.18 (2H, m), 7.55-7.47 (2H, m), 5.25-5.06(2H, m), 5.22 (2H, s), 4.35-4.24 (1H, m), 2.55-2.47 (2H, m), 2.31-1.53(10H, m), 1.44 (9H, s).

Example 2(34)(2S)-N-(4-methoxybenzyl)-3-cyclohexyloxycarbonyl-2-t-butoxycarbonylamino-propanamide

[0579]

[0580] TLC: Rf 0.18 (ethyl acetate:hexane=1:3);

[0581] NMR (CDCl₃): δ 7.18 (2H, d, J=9 Hz), 6.85 (2H, d, J=9 Hz),6.85-6.67 (1H, m), 5.80-5.58 (1H, m), 4.83-4.67 (1H, m), 4.60-4.40 (1H,m), 4.43-4.25 (2H, m), 3.79 (3H, s), 2.98 (1H, dd, J=18, 5 Hz), 2.68(1H, dd, J=18, 5 Hz), 1.95-1.60 (5H, m), 1.60-1.10 (5H, m), 1.42 (9H,s).

Example 2(35)(2S)-3-cyclohexylcarbomoyl-2-t-butoxycarbonylaminopropanoicacid.4-methoxybenzyl ester

[0582]

[0583] TLC: Rf 0.31 (ethyl acetate:hexane=1:3);

[0584] NMR (CDCl₃): δ 7.28 (2H, d, J=9 Hz), 6.87 (2H, d, J=9 Hz),5.85-5.70 (1H, m), 5.53-5.35 (1H, m), 5.14 (1H, d, J=12 Hz), 5.10 (1H,d, J=12 Hz), 4.55-4.43 (1H, m), 3.80 (3H, s), 3.78-3.58 (1H, m), 2.81(1H, dd, J=15, 5 Hz), 2.66 (1H, dd, J=15, 5 Hz), 1.95-1.48 (5H, m),1.48-0.94 (5H, m), 1.42 (9H, s).

Example 2(36)(2S)-N-(4-methoxybenzyl)-3-cyclohexylcarbamoyl-2-t-butoxycarbonylamino-propanamide

[0585]

[0586] TLC: Rf 0.19 (ethyl acetate:hexane=1:3);

[0587] NMR (CDCl₃): δ 7.25-7.10 (1H, m), 7.17 (2H, d, J=9 Hz), 6.84 (2H,d, J=9 Hz), 6.33-6.15 (1H, m), 5.87-5.70 (1H, m), 4.53-4.40 (1H, m),4.36 (2H, d, J=6 Hz), 3.79 (3H, s), 3.78-3.58 (1H, m), 2.84 (1H, dd,J=15, 5 Hz), 2.51 (1H, dd, J=15, 5 Hz), 1.94-1.50 (5H, m), 1.50-0.97(5H, m), 1.42 (9H, s).

Example 2(37)(2S)-N-(4-methoxybenzyl)-3-cyclohexyloxycarbonyl-2-t-butoxycarbonylamino-propanamide

[0588]

[0589] TLC: Rf 0.21 (ethyl acetate:hexane=1:3);

[0590] NMR (CDCl₃): δ 7.18 (2H, d, J=9 Hz), 6.85 (2H, d, J=9 Hz),6.80-6.70 (1H, m), 5.78-5.62 (1H, m), 5.23-5.08 (1H, m), 4.59-4.23 (3H,m), 3.80 (3H, s), 2.96 (1H, dd, J=18, 5 Hz), 2.65 (1H, dd, J=18, 8 Hz),1.93-1.48 (8H, m), 1.42 (9H, s).

Example 2(38)(2S)-3-cyclopentylcarbamoyl-2-t-butoxycarbonylaminopropanoicacid.4-methoxybenzyl ester

[0591]

[0592] TLC: Rf 0.46 (ethyl acetate:hexane=1:);

[0593] NMR (CDCl₃): δ 7.28 (2H, d, J=9 Hz), 6.87 (2H, d, J=9 Hz),5.83-5.73 (1H, m), 5.64-5.47 (1H, m), 5.14 (1H, d, J=12 Hz), 5.09 (1H,d, J=12 Hz), 4.56-4.40 (1H, m), 4.21-4.04 (1H, m), 3.81 (3H, s), 2.79(1H, dd, J=15, 5 Hz), 2.65 (1H, dd, J=15, 5 Hz), 2.05-1.84 (2H, m),1.75-1.48 (4H, m), 1.46-1.17 (2H, m), 1.42 (9H, s).

Example 2(39)(2S)-N-(4-methoxybenzyl)-3-cyclopentylcarbamoyl-2-t-butoxycarbonylamino-propanamide

[0594]

[0595] TLC: Rf 0.33 (methanol:methylene chloride=1:19);

[0596] NMR (CDCl₃): δ 7.23-7.10 (1H, m), 7.17 (2H, d, J=9 Hz), 6.84 (2H,d, J=9 Hz), 6.32-6.15 (1H, m), 6.00-5.82 (1H, m), 4.51-4.31 (3H, m),4.20-4.03 (1H, m), 3.79 (3H, s), 2.83 (1H, dd, J=15, 5 Hz), 2.50 (1H,dd, J=15, 8 Hz), 2.05-1.80 (2H, m), 1.75-1.46 (4H, m), 1.46-1.23 (2H,m), 1.42 (9H, s).

Example 2(40)(2S)-3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.2-pyridylmethyl ester

[0597]

[0598] TLC: Rf 0.41 (hexane:ethyl acetate=2:1);

[0599] NMR (CDCl₃): δ 8.58 (1H, d, J=4.6 Hz), 7.74-7.66 (1H, m), 7.37(1H, d, J=7.8 Hz), 7.23 (1H, dd, J=4.6, 7.8 Hz), 5.55 (1H, d, J=8.8 Hz),5.31 (2H, s), 5.20-5.12 (1H, m), 4.72-4.62 (1H, m), 3.02 (1H, dd, J=4.8,16.8 Hz), 2.81 (1H, dd, J=4.8, 16.8 Hz), 1.84-1.56 (8H, m), 1.44 (9H,s).

Example 2(41)(2S)-3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.4-t-butylbenzyl ester

[0600]

[0601] TLC: Rf 0.45 (hexane:ethyl acetate=6:1);

[0602] NMR (CDCl₃): δ 7.38 (2H, d, J=8.6 Hz), 7.27 (2H, d, J=8.6 Hz),5.49 (1H, d, J=8.6 Hz), 5.21-5.08 (3H, m), 4.62-4.53 (1H, m), 2.96 (1H,dd, J=4.8, 16.8 Hz), 2.77 (1H, dd, J=4.8, 16.8 Hz), 1.76-1.52 (8H, m),1.43 (9H, s), 1.32 (9H, s).

Example 2(42)(2S)-3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.2-methoxybenzyl ester

[0603]

[0604] TLC: Rf 0.32 (hexane:ethyl acetate=4:1);

[0605] NMR (CDCl₃): δ 7.34-7.26 (2H, m), 6.95 (1H, d, J=6.6 Hz), 6.86(1H, d, J=8.4 Hz), 5.50 (1H, d, J=8.8 Hz), 5.23 (2H, s), 5.18-5.10 (1H,m), 4.65-4.56 (1H, m), 3.83 (3H, s), 2.96 (1H, dd, J=4.8, 16.8 Hz), 2.87(1H, dd, J=4.8, 16.8 Hz), 1.84-1.45 (8H, m), 1.44 (9H, s).

Example 2(43)(2S)-3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.3-methoxybenzyl ester

[0606]

[0607] TLC: Rf 0.32 (hexane:ethyl acetate=4:1);

[0608] NMR (CDCl₃): δ 7.31-7.23 (1H, m), 6.93-6.84 (3H, m), 5.50 (1H, d,J=8.8 Hz), 5.22-5.08 (3H, m), 4.64-4.54 (1H, m), 3.81 (3H, s), 2.97 (1H,dd, J=4.8, 16.8 Hz), 2.77 (1H, dd, J=4.8, 16.8 Hz), 1.86-1.50 (8H, m),1.44 (9H, s).

Example 2(44)(2S)-3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.3-pyridylmethyl ester

[0609]

[0610] TLC: Rf 0.36 (hexane:ethyl acetate=1:1);

[0611] NMR (CDCl₃): δ 8.60-8.57 (2H, m), 7.69 (1H, d, J=7.6 Hz),7.33-7.27 (1H, m), 5.50 (1H, d, J=9.4 Hz), 5.28-5.10 (3H, m), 4.64-4.54(1H, m), 2.97 (1H, dd, J=4.8, 17.0 Hz), 2.77 (1H, dd, J=4.8, 17.0 Hz),1.86-1.49 (8H, m), 1.43 (9H, s).

Example 2(45)(2S)-3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.4-pyridylmethyl ester

[0612]

[0613] TLC: Rf 0.29 (hexane:ethyl acetate=1:1);

[0614] NMR (CDCl₃): δ 8.60 (2H, d, J=6.0 Hz), 7.25 (2H, d, J=6.0 Hz),5.54 (1H, d, J=8.8 Hz), 5.28-5.12 (3H, m), 4.70-4.61 (1H, m), 3.02 (1H,dd, J=4.8, 16.8 Hz), 2.80 (1H, dd, J=4.8, 16.8 Hz), 1.87-1.52 (8H, m),1.45 (9H, s).

Example 2(46)(2S)-3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.4-chlorobenzyl ester

[0615]

[0616] TLC: Rf 0.26 (hexane:ethyl acetate=6:1);

[0617] NMR (CDCl₃): δ 7.33 (2H, d, J=8.8 Hz), 7.27 (2H, d, J=8.8 Hz),5.49 (1H, d, J=8.0 Hz), 5.22-5.06 (3H, m), 4.63-4.54 (1H, m), 2.96 (1H,dd, J=4.6, 16.8 Hz), 2.76 (1H, dd, J=4.6, 16.8 Hz), 1.83-1.53 (8H, m),1.44 (9H, s).

Example 2(47)(2S)-3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.4-bromobenzyl ester

[0618]

[0619] TLC: Rf 0.25 (hexane:ethyl acetate=6:1);

[0620] NMR (CDCl₃): δ 7.48 (2H, d, J=8.6 Hz), 7.21 (2H, d, J=8.6 Hz),5.49 (1H, d, J=8.4 Hz), 5.20-5.04 (3H, m), 4.63-4.54 (1H, m), 2.96 (1H,dd, J=4.6, 17.0 Hz), 2.76 (1H, dd, J=4.6, 17.0 Hz), 1.83-1.52 (8H, m),1.43 (9H, s).

Example 2(48)(2S)-4-(pyrrolidin-1-ylcarbonyl)-2-t-butoxycarbonylaminobutanoicacid.4-methoxybenzyl ester

[0621]

[0622] TLC: Rf 0.33 (methylene chloride:methanol=19:1);

[0623] NMR (CDCl₃): δ 7.30 (2H, d, J=9 Hz), 6.87 (2H, d, J=9 Hz),5.58-5.40 (1H, m), 5.15 (1H, d, J=13 Hz), 5.06 (1H, d, J=13 Hz),4.38-4.20 (1H, m), 3.81 (3H, s), 3.48-3.38 (2H, m), 3.32-3.20 (2H, m),2.16-1.78 (8H, m), 1.42 (9H, s).

Example 2(49)(2S)-3-cyclohexylcarbonyloxy-2-t-butoxycarbonylaminopropanoicacid.4-methoxybenzyl ester

[0624]

[0625] TLC: Rf 0.25 (ethyl acetate:hexane=1:5),

[0626] NMR (CDCl₃): δ 7.29 (2H, d, J=9 Hz), 6.88 (2H, d, J=9 Hz), 5.28(1H, d, J=8 Hz), 5.14 (1H, d, J=12 Hz), 5.09 (1H, d, J=12 Hz), 4.64-4.52(1H, m), 4.45 (1H, dd, J=11, 4 Hz), 4.26 (1H, dd, J=11, 4 Hz), 3.81 (3H,s), 2.27-2.10 (1H, m), 1.89-1.53 (5H, m), 1.53-1.05 (5H, m), 1.44 (9H,s).

Example 2(50)(2S)-3-cyclopentyloxycarbonyl-2-(N-methyl-N-t-butoxycarbonylamino)-propanoicacid.4-methoxybenzyl ester

[0627]

[0628] TLC: Rf 0.65 (ethyl acetate:hexane=1:2);

[0629] NMR (CDCl₃): δ 7.31-7.25 (2H, m), 6.91-6.83 (2H, m), 5.23-5.01(3H, m), 4.86-4.55 (1H, m), 3.81 (3H, s), 3.03 (1H, dd, J=16.2, 6.4 Hz),2.91-2.83 (2H, m), 2.71 (1H, dd, J=16.2, 7.8 Hz), 1.96-1.52 (8H, m),1.43-1.38 (9H, m).

Example 2(51)(2S)-3-cyclohexyloxycarbonyl-2-(N-methyl-N-t-butoxycarbonylamino)-propanoicacid.4-methoxybenzyl ester

[0630]

[0631] TLC: Rf 0.75 (ethyl acetate:hexane=1:2);

[0632] NMR (CDCl₃): δ 7.27(2H, d, J=8.6 Hz), 6.87 (2H, d, J=8.6 Hz),5.18-5.01 (2H, m), 4.88-4.55 (2H, m), 3.81 (3H, s), 3.05 (1H, dd,J=16.4, 6.4 Hz), 2.91-2.83 (3H, m), 2.74 (1H, dd, J=16.4, 8.4 Hz),1.89-1.16 (19H, m).

Example 2(52) (2R)-3-cyclohexylmethoxy-2-t-butoxycarbonylaminopropanoicacid.4-methoxybenzyl ester

[0633]

[0634] TLC: Rf 0.18 (ethyl acetate:hexane=1:8);.

[0635] NMR (CDCl₃): δ 7.32-7.25 (2H, m), 6.92-6.85 (2H, m), 5.36 (1H,br. d, J=8.8 Hz), 5.18 (1H, d, J=12.0 Hz), 5.06 (1H, d, J=12.0 Hz),4.48-4.34 (1H, m), 3.81-3.76 (4H, m), 3.60 (1H, dd, J=9.8, 3.2 Hz), 3.19(1H, dd, J=9.4, 6.6 Hz), 3.09 (1H, dd, J=9.4, 6.4 Hz), 1.74-1.13 (19H,m).

Example 2(53) (2S)-3-cyclohexylmethoxy-2-t-butoxycarbonylaminopropanoicacid.4-methoxybenzyl ester

[0636]

[0637] TLC: Rf 0.18 (ethyl acetate:hexane=1:8);

[0638] NMR (CDCl₃): δ 7.32-7.25 (2H, m), 6.92-6.85 (2H, m), 5.36 (1H,br. d, J=8.8 Hz), 5.18 (1H, d, J=12.0 Hz), 5.06 (1H, d, J=12.0 Hz),4.48-4.34 (1H, m), 3.81-3.76 (4H, m), 3.60 (1H, dd, J=9.8, 3.2 Hz), 3.19(1H, dd, J=9.4, 6.6 Hz), 3.09 (1H, dd; J=9.4, 6.4 Hz), 1.74-1.13 (19H,m).

Example 2(54)(2S)-3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.4-methoxyphenethyl ester

[0639]

[0640] TLC: Rf 0.60 (ethyl acetate:hexane=1:2);

[0641] NMR (CDCl₃): δ 7.17-7.09 (2H, m), 6.88-6.80 (2H, m), 5.45 (1H.br. d, J=8.8 Hz), X 4.78-4.65 (1H, m), 4.59-4.49 (1H, m), 4.40-4.22 (2H,m), 3.79 (3H, s), 2.99-2.85 (3H, m), 2.76 (1H, dd, J=17.0, 4.6 Hz),1.86-1.24 (19H, m)

Example 2(55)(2S)-3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.3-(4-methoxyphenyl)propyl ester

[0642]

[0643] TLC: Rf 0.67 (ethyl acetate:hexane=1:2),

[0644] NMR (CDCl₃): δ 7.13-7.05 (2H, m), 6.86-6.79 (2H, m), 5.49 (1H,br. d, J=8.6 Hz), 4.81-4.70 (1H, m), 4.60-4.51 (1H, m), 4.24-4.04 (2H,m), 3.79 (3H, s), 2.98 (1H, dd, J=16.6, 4.6 Hz), 2.79 (1H, dd, J=16.6,4.8 Hz), 2.62 (2H, t, J=7.4 Hz), 2.00-1.16 (21H, m).

Example 2(56)(2S)-3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.furan-2-ylmethyl ester

[0645]

[0646] TLC: Rf 0.63 (ethyl acetate:hexane=1:2);

[0647] NMR (CDCl₃): δ 7.42-7.40 (1H, m), 6.41 (1H, d, J=3.2 Hz), 6.35(1H, dd, J=3.2, 2.0 Hz), 5.46 (1H, d, J=8.6 Hz), 5.12 (2H, s), 4.81-4.67(1H, m), 4.62-4.53 (1H, m), 2.96 (1H, dd, J=16.8, 4.8 Hz), 2.77 (1H, dd,J=16.8, 5.0 Hz), 1.86-1.16 (19H, m).

Example 2(57)(2S)-3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.thiophen-2-ylmethyl ester

[0648]

[0649] TLC: Rf 0.62 (ethyl acetate:hexane=1:2);

[0650] NMR (CDCl₃): δ 7.32 (1H, dd, J=5.0, 1.4 Hz), 7.10-7.08 (1H, m),6.98 (1H, dd, J=5.0, 3.2), 5.48 (1H, d, J=8.4 Hz), 5.37 (1H, d, J=12.8Hz), 5.28 (1H, d, J=12.8 Hz), 4.76-4.66 (1H, m), 4.62-4.53 (1H, m), 2.97(1H, dd, J=17.2, 4.8 Hz), 2.78 (1H, dd, J=17.2, 4.6 Hz), 1.86-1.22 (19H,m).

Example 2(58)(2S)-3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropaniocacid.4-(4-methoxyphenyl)butyl ester

[0651]

[0652] TLC: Rf 0.63 (ethyl acetate:hexane=1:2);

[0653] NMR (CDCl₃): δ 7.12-7.05 (2H, m), 6.86-6.79 (2H, m), 5.47 (1H, d,J=8.8 Hz), 4.79-4.68 (1H, m), 4.58-4.49 (1H, m), 4.18-4.12 (2H, m), 2.96(1H, dd, J=17.2, 4.0 Hz), 2.78 (1H, dd, J=17.2, 4.8 Hz), 2.61-2.54 (2H,m), 1.89-1.16 (23H, m).

Example 2(59)(2S)-3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.cyclohexyl ester

[0654]

[0655] TLC: Rf 0.82 (ethyl acetate:hexane=1:2);

[0656] NMR (CDCl₃): δ 5.48 (1H, d, J=8.4 Hz), 4.88-4.70 (2H, m),4.56-4.47 (1H, m), 2.97 (1H, dd, J=16.6, 4.0 Hz), 2.78 (1H, dd, J=16.6,4.8 Hz), 1.90-1.18 (29H, m).

Example 2(60)(2S)-3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.methyl ester

[0657]

[0658] TLC: Rf 0.55 (ethyl acetate:hexane=1:2);

[0659] NMR (CDCl₃): δ 5.47 (1H, d, J=8.0 Hz), 4.82-4.71 (1H, m),4.62-4.53 (1H, m), 3.76 (3H, s), 2.97 (1H, dd, J=16.8, 4.6 Hz), 2.78(1H, dd, J=16.8, 5.0 Hz), 1.90-1.18 (19H, m).

Example 2(61)(2S)-N-(4-methoxyphenyl)-3-cyclohexyloxycarbonyl-2-t-butoxycarbonylamino-propanamide

[0660]

[0661] TLC: Rf 0.51 (ethyl acetate:hexane=1:2);

[0662] NMR (CDCl₃): δ 8.41 (1H, br. s), 7.45-7.37 (2H, m), 6.89-6.81(2H, m), 5.80 (1H, d, J=7.0 Hz), 4.84-4.73 (1H, m), 4.66-4.57 (1H, m),3.79 (3H, s), 3.01 (1H, dd, J=16.8, 4.4 Hz), 2.73 (1H, dd, J=16.8, 7.0Hz), 1.86-1.16 (19H, m).

Example 2(62)(2S)-3-cyclobutyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.4-methoxybenzyl ester

[0663]

[0664] TLC: Rf 0.57 (ethyl acetate:hexane=1:2);

[0665] NMR (CDCl₃): δ 7.31-7.24 (2H, m), 6.92-6.85 (2H, m), 5.48 (1H, d,J=9.0 Hz), 5.15 (1H, d, J=11.8 Hz), 5.07 (1H, d, J=11.8 Hz), 5.01-4.86(1H, m), 4.62-4.52 (1H, m), 3.81 (3H, s), 2.96 (1H, dd, J=17.2, 5.2 Hz),2.76 (1H, dd, J=17.2, 4.8 Hz), 2.37-2.22 (2H, m), 2.12-1.43 (13H, m).

Example 2(63)(2S)-3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.diphenylmethyl ester

[0666]

[0667] TLC: Rf 0.33 (ethyl acetate:hexane=1:5);

[0668] NMR (CDCl₃): δ 7.45-7.18 (10H, m), 6.90 (1H, s), 5.56 (1H, d, J=8Hz), 4.75-4.58 (2H, m), 3.03 (1H, dd, J=18, 5 Hz), 2.83 (1H, dd, J=18, 5Hz), 1.80-1.08 (10H, m), 1.43 (9H, s).

Example 2(64)(2S)-N-((1S)-2-phenyl-1-benzyloxycarbonylethyl)-3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanamide

[0669]

[0670] TLC: Rf 0.53 (ethyl acetate:hexane=1:2);

[0671] NMR (CDCl₃): δ 7.39-7.19 (8H, m), 7.08-7.03 (2H, m), 6.97 (1H, d,J=8.4 Hz), 5.61 (1H, d, J=8.4 Hz), 5.14 (1H, d, J=12.4 Hz), 5.08 (1H, d,J=12.4 Hz), 4.90-4.69 (2H, m), 4.56-4.42 (1H, m), 3.10 (2H, d, J=6.0Hz), 2.93 (1H, dd, J=17.2, 4.6 Hz), 2.62 (1H, dd, J=17.2, 6.2 Hz),1.89-1.18 (19H, m).

Example 2(65)(2S)-N-((1S)-1-benzyloxycarbonylethyl)-3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanamide

[0672]

[0673] TLC: Rf 0.47 (ethyl acetate:hexane=1:2);

[0674] NMR (CDCl₃): δ 7.41-7.31 (5H, m), 7.09 (1H, d, J=6.4 Hz), 5.67(1H, d, J=7.8 Hz), 5.20 (1H, d, J=12.0 Hz), 5.13 (1H, d, J=12.0 Hz),4.81-4.46 (3H, m), 2.96 (1H, dd, J=16.8, 4.4 Hz), 2.64 (1H, dd, J=16.8,6.6), 1.92-1.18 (19H, m).

Example 2(66) (2S)-3-benzyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.4-methoxybenzyl ester

[0675]

[0676] TLC: Rf 0.33 (ethyl acetate:hexane=1:3);

[0677] NMR (CDCl₃): δ 7.40-7.27 (5H, m), 7.23 (2H, d, J=9 Hz), 6.85 (2H,d, J=9 Hz), 5.56-5.40 (1H, m), 5.07 (4H, s), 4.65-4.50 (1H, m), 3.80(3H, s), 3.03 (1H, dd, J=18, 5 Hz), 2.85 (1H, dd, J=18, 5 Hz), 1.42 (9H,s).

Example 2(67)(2S)-3-cycloheptyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.4-methoxybenzyl ester

[0678]

[0679] TLC: Rf 0.36 (hexane:ethyl acetate=4:1);

[0680] NMR (CDCl₃): δ 7.27 (2H, d, J=8.4 Hz), 6.88 (2H, d, J=8.4 Hz),5.48 (1H, d, J=8.4 Hz), 5.15 (1H, d, J=12.2 Hz), 5.07 (1H, d, J=12.2Hz), 4.94-4.82 (1H, m), 4.61-4.52 (1H, m), 3.81 (3H, s), 2.95 (1H, dd,J=4.4, 16.8 Hz), 2.76 (1H, dd, J=4.8, 16.8 Hz), 1.90-1.75 (2H, m),1.68-1.34 (19H, m).

Example 2(68)(2S)-3-cyclooctyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.4-methoxybenzyl ester

[0681]

[0682] TLC: Rf 0.38 (hexane:ethyl acetate=4:1);

[0683] NMR (CDCl₃): δ 7.27 (2H, d, J=8.4 Hz), 6.88 (2H, d, J=8.4 Hz),5.49 (1H, d, J=8.4 Hz), 5.16 (1H, d, J=12.0 Hz), 5.07 (1H, d, J=12.0Hz), 4.96-4.84 (1H, m), 4.61-4.52 (1H, m), 3.81 (3H, s), 2.94 (1H, dd,J=4.4, 16.8 Hz), 2.75 (1H, dd, J=4.8, 16.8 Hz), 1.75-1.46 (14H, m), 1.43(9H, s).

Example 2(69)(2S)-3-(adamantan-2-yloxycarbonyl)-2-t-butoxycarbonylaminopropanoicacid.4-methoxybenzyl ester

[0684]

[0685] TLC: Rf 0.43 (hexane:ethyl acetate=4:1);

[0686] NMR (CDCl₃): δ 7.27 (2H, d, J=8.6 Hz), 6.87 (2H, d, J=8.6 Hz),5.51 (1H, d, J=8.4 Hz), 5.16 (1H, d, J=12.0 Hz), 5.06 (1H, d, J=12.0Hz), 4.92-4.87 (1H, br), 4.63-4.54 (1H, m), 3.81 (3H, s), 3.01 (1H, dd,J=4.6, 16.8 Hz), 2.83 (1H, dd, J=4.8, 16.8 Hz), 2.01-1.67 (12H, m),1.58-1.45 (2H, m), 1.43 (9H, s).

Example 2(70)(2S)-3-(adamantan-1-yloxycarbonyl)-2-t-butoxycarbonylaminopropanoicacid.4-methoxybenzyl ester

[0687]

[0688] TLC: Rf 0.42 (hexane:ethyl acetate=4:1);

[0689] NMR (CDCl₃): δ 7.29 (2H, d, J=8.6 Hz), 6.87 (2H, d, J=8.6 Hz),5.49 (1H, d, J=8.4 Hz), 5.17 (1H, d, J=11.9 Hz), 5.05 (1H, d, J=11.9Hz), 4.57-4.48 (1H, m), 3.80 (3H, s), 2.90 (1H, dd, J=4.4, 16.8 Hz),2.69 (1H, dd, J=4.8, 16.8 Hz), 2.18-2.07 (3H, br), 2.01 (6H, d, J=3.0Hz), 1.63 (6H, t, J=3.0 Hz), 1.44 (9H, s).

Example 2(71) (2S,3R)-3-cyclohexylcarbonyloxy-2-t-butoxycarbonylaminobutanoicacid.4-methoxybenzyl ester

[0690]

[0691] TLC: Rf 0.35 (ethyl acetate:hexane=1:5);

[0692] NMR (CDCl₃): δ 7.29 (2H, d, J=9 Hz), 6.88 (2H, d, J=9 Hz),5.46-5.30 (1H, m), 5.17 (1H, d, J=10 Hz), 5.06 (1H, d, J=13 Hz), 5.04(1H, d, J=13 Hz), 4.44 (1H, dd, J=10, 2 Hz), 3.81 (3H, s), 2.20-2.00(1H, m), 1.85-1.50 (5H, m), 1.46 (9H, s), 1.40-1.00 (5H, m), 1.25 (3H,d, J=6 Hz).

Example 2(72)(2S)-N-((1S)-1-(4-methoxybenzyloxycarbonyl)ethyl)-3-cyclohexyloxycarbonyl-2-benzyloxycarbonylaminopropanamide

[0693]

[0694] TLC: Rf 0.31 (ethyl acetate:hexane=1:2);

[0695] NMR (CDCl₃): δ 7.39-7.24 (7H, m), 7.03 (1H, d, J=7.2 Hz),6.92-6.85 (2H, m), 5.91 (1H, d, J=7.8 Hz), 5.16-5.03 (4H, m), 4.82-4.69(1H, m), 4.64-4.47 (2H, m), 3.81 (3H, s), 2.99 (1H, dd, J=17.2, 4.0 Hz),2.65 (1H, dd, J=17.2, 6.4 Hz), 1.84-1.18 (13H, m).

Example 2(73)(2S)-N-((1S)-2-phenyl-1-(4-methoxybenzyloxycarbonyl)ethyl)-3-cyclohexyl-oxycarbonyl-2-benzyloxycarbonylaminopropanamide

[0696]

[0697] TLC: Rf 0.36 (ethyl acetate:hexane=1:2);

[0698] NMR (CDCl₃): δ 7.38-7.33 (5H, m), 7.25-7.16 (5H, m), 7.05-6.84(5H, m), 5.87 (1H, d, J=8.2 Hz), 5.15-4.98 (4H, m), 4.86-4.67 (2H, m),4.59-4.50 (1H, m), 3.82 (3H, s), 3.06 (2H, d, J=6.0 Hz), 2.94 (1H, dd,J=17.2, 4.4 Hz), 2.62 (1H, dd, J=17.2, 6.6 Hz), 1.84-1.18 (10H, m).

Example 2(74) (3S)-3-t-butoxycarbonylamino-3-(1, 2, 3,4-tetrahydroquinolin-1-ylcarbonyl)-propanoic acid.cyclohexyl ester

[0699]

[0700] TLC: Rf 0.48 (ethyl acetate:hexane=1:2);

[0701] NMR (DMSO-d₆): 7.50-7.05 (5H, m), 4.97 (1H, dd, J=15.4, 7.0 Hz),4.67-4.52 (1H, m), 3.83-3.50 (2H, m), 2.70-2.38 (4H, m), 1.94-1.80 (2H,m), 1.75-1.18 (19H, m).

Example 2(75) (3S)-3t-butoxycarbonylamino-3-(1, 2, 3,4-tetrahydroisoquinolin-2-yl-carbonyl)propanoic acid.cyclohexyl ester

[0702]

[0703] TLC: Rf 0.42 (ethyl acetate:hexane=1:2);

[0704] NMR (CDCl₃): δ 7.23-7.11 (4H, m), 5.42 (1H, d, J=9.2 Hz),5.14-5.03 (1H, m), 4.88-4.58 (3H, m), 4.02-3.71 (2H, m), 2.97-2.55 (4H,m), 1.92-1.08 (19H, m).

Example 2(76) (2S)-N-methyl-N-(1,1-dimethyl-2-phenylethyl)-3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanamide

[0705]

[0706] TLC: Rf 0.56 (ethyl acetate:hexane=1:2);

[0707] NMR (CDCl₃): δ 7.31-7.09 (5H, m), 5.39 (1H, d, J=9.2 Hz),4.99-4.88 (1H, m>, 4.81-4.71 (1H, m), 3.35 (1H, d, J=13.2 Hz), 3.00 (1H,d, J=13.2 Hz), 2.73 (1H, dd, J=15.4, 6.6 Hz), 2.65 (3H, s), 2.54 (1H,dd, J=15.4, 6.6 Hz), 1.93-1.19 (25H, m).

Example 2(77)(2S)-6-cyclohexylcarbonylamino-2-t-butoxycarbonylaminohexanoidacid.4-methoxybenzyl ester

[0708]

[0709] TLC: Rf 0.37 (ethyl acetate:hexane=1:1);

[0710] NMR (CDCl₃): δ 7.32-7.25 (2H, m), 6.93-6.85 (2H, m), 5.55-5.44(1H, m), 5.17-5.03 (3H, m), 4.35-4.21 (1H, m), 3.81 (3H, s), 3.23-3.14(2H, m), 2.08-1.96 (1H, m), 1.88-1.18 (25H, m).

Example 2(78)(2R)-3-(4-methoxybenzylthio)-2-t-butoxycarbonylaminopropanoicacid.cyclohexyl ester

[0711]

[0712] TLC: Rf 0.70 (ethyl acetate:hexane=1:2);

[0713] NMR (CDCl₃): δ 7.28-7.19 (2H, m), 6.88-6.81 (2H, m), 5.29 (1H, d,J=7.4 Hz), 4.90-4.77 (1H, m), 4.54-4.44 (1H, m), 3.79 (3H, s), 3.70 (2H,s), 2.89 (1H, dd, J=14.0, 4.4 Hz), 2.79 (1H, dd, J=14.0, 6.0 Hz),1.92-1.18 (19H, m).

Example 2(79)(2R)-N-(4-methoxybenzyl)-3-(4-methoxybenzylthio)-2-t-butoxycarbonyl-aminopropanamide

[0714]

[0715] TLC: Rf 0.28 (ethyl acetate:hexane=1:2);

[0716] NMR (CDCl₃): δ 7.26-7.16 (4H, m), 6.89-6.78 (4H, m), 6.53-6.41(1H, m), 5.26 (1H, d, J=7.4 Hz), 4.38 (2H, d, J=5.4 Hz), 4.27-4.18 (1H,m), 3.79 (3H, s), 3.78 (3H, s), 3.68 (2H, s), 2.91 (1H, dd, J=14.0, 5.4Hz), 2.74 (1H, dd, J=14.0, 6.8 Hz), 1.43 (9H, s).

Example 2(80)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-t-butoxycarbonylamino-propanamide

[0717]

[0718] TLC: Rf 0.48 (ethyl acetate:hexane=1:2);

[0719] NMR (CDCl₃): δ 7.25-7.18 (2H, m), 6.89-6.84 (2H, m), 6.68-6.60(1H, m), 5.36 (1H, d, J=7.0 Hz), 4.39 (2H, d, J=5.6 Hz), 4.28-4.18 (1H,m), 3.80 (3H, s), 2.98 (1H, dd, J=14.0, 5.8 Hz), 2.82 (1H, dd, J=14.0,7.0 Hz), 2.46 (1H, dd, J=12.8, 7.0 Hz), 2.39 (1H, dd, J=12.8, 6.6 Hz),1.83-0.82 (20H, m).

Example 2(81)(2S)-N-(4-methoxybenzyl)-3-benzyloxy-2-t-butoxycarbonylaminopropanamide

[0720]

[0721] TLC: Rf 0.26 (ethyl acetate:hexane=1:2);

[0722] NMR (CDCl₃): δ 7.38-7.12 (7H, m), 6.84-6.77 (2H, m), 6.69-6.61(1H, m), 5.44-5.34 (1H, m), 4.56 (1H, d, J=11.4 Hz), 4.47 (1H, d, J=11.4Hz), 4.39 (2H, d, J=5.8 Hz), 4.34-4.24 (1H, m), 3.95 (1H, dd, J=9.2, 3.8Hz), 3.78 (3H, s), 3.59 (1H, dd, J=9.2, 6.6 Hz), 1.43 (9H, s).

Example 2(82)(2S)-N-(4-dimethylaminobenzyl)-3-cyclohexylmethoxy-2-t-butoxycarbonyl-aminopropanamide

[0723]

[0724] TLC: Rf 0.42 (ethyl acetate:hexane=1:2);

[0725] NMR (CDCl₃): δ 7.18-7.11 (2H, m), 6.72-6.56 (3H, m), 5.46-5.30(1H, m), 4.41 (1H, dd, J=14.2, 5.4 Hz), 4.30 (1H, dd, J=14.2, 5.2 Hz),4.29-4.15 (1H, m), 3.82 (1H, dd, J=9.2, 3.6 Hz), 3.47 (1H, dd, J=9.2,6.8), 3.31-3.16 (2H, m), 2.93 (6H, s), 1.75-0.74 (20H, m).

Example 2(83)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethoxy-2-t-butoxycarbonylamino-propanamide

[0726]

[0727] TLC: Rf 0.18 (ethyl acetate:hexane=1:2);

[0728] NMR (CDCl₃): δ 7.23-7.16 (2H, m), 6.89-6.82 (2H, m), 6.78-6.68(1H, m), 5.46-5.28 (1H, m), 4.45 (1H, dd, J=14.2, 5.4 Hz), 4.35 (1H, dd,J=14.2, 5.6 Hz), 4.28-4.16 (1H, m), 3.86-3.79 (4H, m), 3.47 (1H, dd,J=9.2, 7.0 Hz), 3.27 (1H, dd, J=8.8, 6.4 Hz), 3.20 (1H, dd, J=8.8, 6.2Hz), 1.75-0.74 (20H, m).

Example 2(84)(2S)-N-methyl-N-(4-methoxybenzyl)-3-cyclohexylmethoxy-2-t-butoxycarbonyl-aminopropanamide

[0729]

[0730] TLC: Rf 0.56 (ethyl acetate:hexane=1:2);

[0731] NMR (CDCl₃): δ 7.21-7.13 (2H, m), 6.89-6.80 (2H, m), 5.47-5.38(1H, m), 5.00-4.70 (2H, m), 4.45 (0.3H, d, J=16.6 Hz), 4.30 (0.7H, d,J=14.4 Hz), 3.79 (3H, s), 3.66-3.47 (2H, m), 3.22-3.14 (2H, m), 3.01(2.1H, s), 2.89 (0.9H, s), 1.74-0.74 (20H, m).

Example 2(85)(2RS)-N-(4-methoxybenzyl)-4-cyclohexylmethoxy-2-t-butoxycarbonylamino-butanamide

[0732]

[0733] TLC: Rf 0.24 (ethyl acetate:hexane=1:2);

[0734] NMR (CDCl₃): δ 7.20 (2H, d, J=9 Hz), 6.86 (2H, d, J=9 Hz),6.83-6.68 (1H, m), 6.00-5.85 (1H, m), 4.39 (2H, d, J=6 Hz), 4.37-4.17(1H, m), 3.80 (3H, s), 3.62-3.43 (2H, m), 3.13 (2H, d, J=6 Hz),2.16-1.97 (2H, m), 1.80-1.00 (9H, m), 1.42 (9H, s), 1.00-0.70 (2H, m).

Example 2(86)(2S)-N-(4-nitrobenzyl)-3-cyclohexylmethoxy-2-t-butoxycarbonylamino-propanamide

[0735]

[0736] TLC: Rf 0.28 (ethyl acetate:hexane=1:2)

[0737] NMR (CDCl₃): δ 8.22-8.14 (2H, m), 7.48-7.41 (2H, m), 7.02-6.94(1H, m), 5.37 (1H, d, J=6.4 Hz), 4.64 (1H, dd, J=13.2, 5.8 Hz), 4.53(1H, dd, J=13.2, 6.2 Hz), 4.34-4.22 (1H, m), 3.87 (1H, dd, J=9.2, 3.6Hz), 3.52 (1H , dd, J=9.2, 6.6 Hz), 3.30 (1H, dd, J=9.2, 6.2 Hz), 3.24(1H, dd, J=9.2, 6.0 Hz), 1.77-0.78 (20H, m).

Example 2(87)(2S)-N-(4-methoxybenzyl)-3-(2-cyclohexenyloxy)-2-t-butoxycarbonylamino-propanamide

[0738]

[0739] TLC: Rf 0.26 (ethyl acetate:hexane=1:2);

[0740] NMR (CDCl₃): δ 7.20 (2H, d, J=9 Hz), 6.84 (2H, d, J=9 Hz),6.84-6.59 (1H, m), 5.90-5.78 (1H, m), 5.74-5.60 (1H, m), 5.52-5.34 (1H,m), 4.41 (2H, d, J=6 Hz), 4.30-4.15 (1H, m), 4.00-3.83 (2H, m), 3.79(3H, s), 3.64-3.48 (1H, m), 2.05-1.90 (2H, m), 1.90-1.35 (4H, m), 1.43(9H, S).

Example 2(88)(2S)-N-(4-methoxybenzyl)-3-cyclohexyloxy-2-t-butoxycarbonylamino-propanamide

[0741]

[0742] TLC: Rf 0.28 (ethyl acetate:hexane=1:2);

[0743] NMR (CDCl₃): δ 7.20 (2H, d, J=9 Hz), 6.85 (2H, d, J=9 Hz),6.85-6.70 (1H, m), 5.50-5.30 (1H, m), 4.41 (2H, d, J=6 Hz), 4.26-4.14(1H, m), 3.88 (1H, dd, J=9, 14 Hz), 3.80 (3H, s), 3.50 (1H, dd, J=9, 7Hz), 3.36-3.20 (1H, m), 1.90-1.05 (10H, m), 1.44 (9H, s).

Example 2(89)(2S)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-t-butoxycarbonylamino-propanamide

[0744]

[0745] TLC: Rf 0.43 (ethyl acetate:hexane=1:2);

[0746] NMR (CDCl₃): δ 7.25-7.18 (2H, m), 6.90-6.82 (2H, m), 6.68-6.58(1H, m), 5.35 (1H, d, J=7.4 Hz), 4.40 (2H, d, J=6.0 Hz), 4.28-4.18 (1H,m), 3.80 (3H, s), 2.99 (1H, dd, J=13.6, 5.6 Hz), 2.82 (1H, dd, J=13.6,7.0 Hz), 2.48 (1H, dd, J=12.8, 7.0), 2.39 (1H, dd, J=12.8, 6.6 Hz),1.86-0.80 (20H, m).

Example 2(90)(2R)-N-(4-methoxybenzyl)-3-cyclopentylmethylthio-2-t-butoxycarbonylamino-propanamide

[0747]

[0748] TLC: Rf 0.36 (ethyl acetate:hexane=1:2);

[0749] NMR (CDCl₃): δ 7.25-7.18 (2H, m), 6.89-6.82 (2H, m), 6.68-6.59(1H, m), 5.36 (1H, d, J=7.4 Hz), 4.39 (2H, d, J=5.6 Hz), 4.29-4.19 (1H,m), 3.80 (3H, s), 3.00 (1H, dd, J=13.6, 5.4 Hz), 2.84 (1H, dd, J=13.6,6.6 Hz), 2.54 (2H, d, J=7.4 Hz), 2.10-1.95 (1H, m), 1.91-1.08 (17H, m).

Example 2(91)(2S)-N-(4-methoxybenzyl)-3-cyclopentylmethoxy-2-t-butoxycarbonylamino-propanamide

[0750]

[0751] TLC: Rf 0.33 (ethyl acetate:hexane=1:2);

[0752] NMR (CDCl₃): δ 7.25-7.16 (2H, m), 7.01-6.82 (2H, m), 6.81-6.69(1H, m), 5.42 (1H, d, J=5.8 Hz), 4.44 (1H, dd, J=15.4, 6.0 Hz), 4.37(1H, dd, J=15.4, 5.8 Hz), 4.29-4.18 (1H, m), 3.84 (1H, dd, J=9.2, 3.8Hz), 3.80 (3H , s), 3.50 (1H, dd, J=9.2, 7.0 Hz), 3.37 (1H, dd, J=16.8,7.4 Hz), 3.28 (1H, dd, J=16.8, 6.8 Hz), 2.14-1.99 (1H, m), 1.75-0.83(17H, m).

Example 2(92)(2S)-N-(4-methoxybenzyl)-3-cyclohexylcarbonylamino-2-t-butoxycarbonyl-aminopropanamide

[0753]

[0754] TLC: Rf 0.20 (ethyl acetate:hexane=1:1);

[0755] NMR (CDCl₃+CD₃OD): δ 7.22-7.14 (2H, m), 6.87-6.80 (2H, m), 4.40(1H, d, J=14.8 Hz), 4.29 (1H, d, J=14.8 Hz), 4.25-4.20 (1H m), 3.78 (3H,s), 3.72-3.48 (2H, m), 2.09-1.97 (1H, m), 1.86-1.16 (19H, m).

Example 2(93)(2S)-N-(4-methoxybenzyl)-4-(2-cyclohexenyloxy)-2-t-butoxycarbonylamino-butanamide

[0756]

[0757] TLC: Rf 0.19 (ethyl acetate:hexane=1; 2);

[0758] NMR (CDCl₃): δ 7.24-7.15 (2H, m), 6.94-6.78 (3H, m), 5.94-5.74(2H, m), 5.72-5.60 (1H, m), 4.50-4.15 (3H, m), 3.82-3.52 (3H, m), 3.80(3H, s), 2.13-1.90 (4H, m), 1.80-1.35 (4H, m), 1.42 (9H, s).

Example 2(94)(2S)-N-(4-methoxybenzyl)-4-cyclohexyloxy-2-t-butoxycarbonylamino-butanamide

[0759]

[0760] TLC: Rf 0.21 (ethyl acetate:hexane=1:2);

[0761] NMR (CDCl₃): δ 7.25-7.15 (2H, m), 7.00-6.80 (3H, m), 6.03-5.88(1H, m), 4.52-4.15 (3H, m), 3.80 (3H, s), 3.71-3.42 (2H, m), 3.26-3.08(1H, m), 2.10-1.95 (2H, m), 1.85-1.05 (10H, m), 1.42 (9H, s).

Example 2(95)(2S)-N-(4-methoxybenzyl)-3-cyclopentylmethylthio-2-t-butoxycarbonylamino-propanamide

[0762]

[0763] TLC: Rf 0.53 (ethyl acetate:chloroform=15:100);

[0764] NMR (CDCl₃): δ 7.25-7.18 (2H, m), 6.90-6.82 (2H, m), 6.64 (1H, t,J=6.0 Hz), 5.36 (1H, d, J=7.2 Hz), 4.39 (2H, d, J=6.0 Hz), 4.29-4.19(1H, m), 3.80 (3H, s), 3.00 (1H, dd, J=14.0, 5.4 Hz), 2.84 (1H, dd,J=14.0, 7.0 Hz), 2.54 (2H, d, J=7.0 Hz), 2.13-1.91 (1H, m), 1.90-1.08(17H, m).

Example 2(96)(2R)-N-(4-nitrobenzyl)-3-cyclohexylmethoxy-2-t-butoxycarbonylamino-propanamide

[0765]

[0766] TLC: Rf 0.21 (ethyl acetate:hexane=1:2);

[0767] NMR (CDCl₃): δ 8.21-8.14 (2H, m), 7.48-7.41 (2H, m), 7.03 (1H, t,J=5.8 Hz), 5.39 (1H, d, J=6.2 Hz), 4.63 (1H, dd, J=16.2, 5.8 Hz), 4.53(1H, dd, J=16.2, 6.2 Hz), 4.36-4.22 (1H, m), 3.87 (1H, dd, J=9.0, 3.6Hz), 3.53 (1H, dd, J=9.2, 6.6 Hz), 3.30 (1H, dd, J=9.2, 6.2 Hz), 3.24(1H, dd, J=9.2, 6.2 Hz), 1.79-0.76 (20H, m).

Example 2(97)(2R)-N-(4-nitrobenzyl)-3-cyclohexylmethylthio-2-t-butoxycarbonylamino-propanamide

[0768]

[0769] TLC: Rf 0.40 (ethyl acetate:hexane=1:2);

[0770] NMR (CDCl₃): δ 8.19-8.14 (2H, m), 7.48-7.43 (2H, m), 7.12 (1H, t,J=6.0 Hz), 5.44 (1H, d, J=7.2 Hz), 4.66-4.47 (2H, m), 4.36-4.25 (1H, m),2.98 (1H, dd, J=13.8, 5.8 Hz), 2.86 (1H, dd, J=13.8, 6.6 Hz), 2.56-2.33(2H, m), 1.95-0.71 (20H, m).

Example 2(98)(2R)-N-(furan-2-ylmethyl)-3-cyclohexylmethylthio-2-t-butoxycarbonylamino-propanamide

[0771]

[0772] TLC: Rf 0.60 (ethyl acetate:hexane=1:2);

[0773] NMR (CDCl₃): δ 7.37-7.34 (1H, m), 6.76-6.71 (1H, m), 6.33 (1H,dd, J=5.0, 1.8 Hz), 6.26-6.23 (1H, m), 5.35 (1H, d, J=7.2 Hz), 4.51 (1H,dd, J=15.4, 5.4 Hz), 4.40 (1H, dd, J=5.4, 5.4 Hz), 4.28-4.18 (1H, m),2.98 (1H, dd, J=13.8, 5.4 Hz), 2.81 (1H, dd, J=13.8, 7.0 Hz), 2.45 (1H,dd, J=12.6, 7.0 Hz), 2.39 (1H, dd, J=12.6, 6.6 Hz), 1.88-0.78 (20H, m).

Example 2(99)(2R)-N-(4-dimethylaminobenzyl)-3-cyclohexylmethylthio-2-t-butoxycarbonyl-aminopropanamide

[0774]

[0775] TLC: Rf 0.43 (ethyl acetate:hexane=1:2);

[0776] NMR (CDCl₃): δ 7.20-7.12 (2H, m), 6.73-6.67 (2H, m), 6.55-6.51(1H, m), 5.35 (1H, d, J=7.4 Hz), 4.44-4.17 (3H, m), 2.98 (1H, dd,J=13.8, 5.4 Hz), 2.94 (6H, s), 2.82 (1H, dd, J=13.8, 7.0 Hz), 2.51-2.34(2H, m), 1.88-0.79 (20H, m).

Example 2(100)(2R)-2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanoicacid.4-methoxybenzyl ester

[0777]

[0778] TLC: Rf 0.68 (ethyl acetate:hexane=1:2);

[0779] NMR (CDCl₃): δ 7.34-7.25 (2H, m), 6.92-6.85 (2H, m), 5.36 (1H, d,J=8.0 Hz), 5.16 (1H, d, J=11.6 Hz), 5.08 (1H, d, J=11.6 Hz), 4.57-4.48(1H, m), 3.81 (3H, s), 2.93 (2H, d, J=4.8 Hz), 2.35 (2H, d, J=7.0 Hz),1.85-0.75 (20H, m).

Example 2(101)(2R)-N-(4-methoxycyclohexylmethyl)-2-t-butoxycarbonylamino-3-cyclohexyl-methylthiopropanamide

[0780]

[0781] (The relative configuration of cyclohexyl ring substituted bymethoxy group is not determined, but the above compound is a singlecompound. This compound is the isomer of the compound prepared inExample 2(102).)

[0782] TLC: Rf 0.40 (ethyl acetate:hexane=1:2);

[0783] NMR (CDCl₃): δ 6.47 (1H, t, J=6.0 Hz), 5.37 (1H, d, J=7.4 Hz),4.22-4.12 (1H, m), 3.46-3.36 (1H, m), 3.29 (3K, s), 3.17-3.09 (2H, m),2.95 (1H, dd, J=13.6, 5.6 Hz), 2.78 (1H, dd, J=13.6, 6.8 Hz), 2.54-2.38(2H, m), 2.00-0.81 (29H, m).

Example 2(102)(2R)-N-(4-methoxycyclohexylmethyl)-2-t-butoxycarbonylamino-3-cyclohexyl-methylthiopropanamide

[0784]

[0785] (The relative configuration of cyclohexyl ring substituted bymethoxy group is not determined, but the above compound is a singlecompound. This compound is the isomer of the compound prepared inExample 2(101).)

[0786] TLC: Rf 0.30 (ethyl acetate:hexane=1:2),

[0787] NMR (CDCl₃): δ 6.46 (1H, t, J=5.6 Hz), 5.36 (1H, d, J=7.0 Hz),4.22-4.12 (1H, m), 3.34 (3H, s), 3.17-2.91 (4H, m), 2.79 (1H, dd,J=13.8, 7.0 Hz), 2.54-2.38 (2H, m), 2.15-2.01 (2H, m), 1.89-0.82 (27H,m).

Example 2(103)(2R)-N-(4-phenoxybenzyl)-2-t-butoxycarbonylamino-3-cyclohexylmethyl-thiopropanamide

[0788]

[0789] NMR (CDCl₃): δ 7.39-7.22 (m, 4H), 7.15-7.06 (m, 1H), 7.03-6.93(m, 4H), 6.70 (t, J=5.3 Hz, 1H), 5.35 (d, J=6.8 Hz, 1H), 4.44 (d, J=6.0Hz, 2H), 4.30-4.20 (m, 1H), 2.99 (dd, J=14.0, 5.6 Hz, 1H), 2.83 (dd,J=14.0, 7.0 Hz, 1H), 2.52-2.36 (m, 2H), 1.88-0.79 (m, 20H).

Example 2(104)(2R)-N-((1S)-1-(4-nitrophenyl)ethyl)-2-t-butoxycarbonylamino-3-cyclohexyl-methylthiopropanamide

[0790]

[0791] TLC: Rf 0.46 (ethyl acetate:hexane=1:2)

[0792] NMR (CDCl₃): δ 8.25-8.15 (2H, m), 7.54-7.45 (2H, m), 6.84 (1H, d,J=7 Hz), 5.36 (1H, d, J=7 Hz), 5.15 (1H, quintet, J=7 Hz), 4.21 (1H, td,J=7, 5 Hz), 2.93 (1H, dd, J=14, 5 Hz), 2.79 (1H, dd, J=14, 7 Hz), 2.44(2H, d, J=7 Hz), 1.88-0.78 (11H, m), 1.52 (3H, d, J=7 Hz), 1.46 (9H, s).

Example 2(105)(2R)-N-((1R)-1-(4-nitrophenyl)ethyl)-2-t-butoxycarbonylamino-3-cyclohexyl-methylthiopropanamide

[0793]

[0794] TLC: Rf 0.47 (ethyl acetate:hexane=1:2);

[0795] NMR (CDCl₃): δ 8.22-8.15 (2H, m), 7.51-7.44 (2H, m), 6.89 (1H, d,J=7.8 Hz), 5.32 (1H, d, J=7.0 Hz), 5.21-5.06 (1H, m), 4.27-4.17 (1H, m),2.95 (1H, dd, J=14.0, 5.8 Hz), 2.80 (1H, dd, J=14.0, 7.0 Hz), 2.44 (1H,dd, J=12.4, 6.8 Hz), 2.38 (1H, dd, J=12.4, 6.6 Hz), 1.88-0.80 (23H, m).

Example 2(106)(2R)-N-methyl-N-(4-nitrobenzyl)-2-t-butoxycarbonylamino-3-cyclohexyl-methylthiopropanamide

[0796]

[0797] TLC: Rf 0.37 (ethyl acetate:hexane=1:2);

[0798] NMR (CDCl₃): δ 8.25-8.16 (2H, m), 7.48-7.41 (2H, m), 5.38-5.25(1H, m), 4.95-4.60 (3H, m), 3.14 (2.33H, s), 2.98 (0.67H, s), 2.96-2.66(2H, m), 2.46 (1.56H, d, J=6.6 Hz), 2.33 (0.44H, d, J=6.6 Hz), 1.88-0.81(20H, m).

Example 2(107)(2R)-N-(1-(4-methoxyphenyl)-1-methylethyl)-2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide

[0799]

[0800] TLC: Rf 0.21 (ethyl acetate:hexane=1:5);

[0801] NMR (CDCl₃): δ 7.37-7.26 (2H, m), 6.89-6.79 (2H, m), 6.70 (1H,bs), 5.36 (1H, d, J=8 Hz), 4.11 (1H, td, J=7, 5 Hz), 3.80 (3H, s), 2.91(1H, dd, J=14, 5 Hz), 2.75 (1H, dd, J=14, 7 Hz), 2.47 (2H, d, J=7 Hz),1.90-0.80 (11H, m), 1.70 (3H, s), 1.69 (3H, s), 1.47 (9H, s).

Example 2(108)(2R)-N-(1-methyl-1-(4-nitrophenyl)ethyl)-2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide

[0802]

[0803] TLC: Rf 0.34 (ethyl acetate:hexane=1:3);

[0804] NMR (CDCl₃): δ 8.22-8.12 (2H, m), 7.60-7.49 (2H, m), 6.89 (1H,bs), 5.31 (1H, d, J=8 Hz), 4.14 (1H, td, J=7, 5 Hz), 2.90 (1H, dd, J=14,5 Hz), 2.75 (1H, dd, J=14, 7 Hz), 2.47 (2H, d, J=7 Hz), 1.90-0.80 (11H,m), 1.71 (3H, s), 1.70 (3H, s), 1.50 (9H, s).

Example 2(109)(2S)-N-((1R)-1-(4-nitrophenyl)ethyl)-2-t-butoxycarbonylamino-3-cyclohexyl-methylthiopropanamide

[0805]

[0806] TLC: Rf 0.37 (ethyl acetate:hexane=1:2);

[0807] NMR (CDCl₃): δ 8.23-8.16 (2H, m), 7.53-7.46 (2H, m), 6.83 (1H, d,J=7.4 Hz), 5.36 (1H, d, J=7.4 Hz), 5.22-5.08 (1H, m), 4.25-4.16 (1H, m),2.94 (1H, dd, J=13.6, 5.6 Hz) 2.78 (1H, dd, J=13.6, 7.0 Hz), 2.44 (2H,d, J=6.8 Hz), 1.88-0.80 (23H, m).

Example 2(110)(2R)-N-methyl-N-(4-methoxybenzyl)-2-t-butoxycarbonylamino-3-cyclohexyl-methylthiopropanamide

[0808]

[0809] TLC: Rf 0.44 (ethyl acetate:hexane=1:2).

Example 2(111)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(N′-methyl-N′-(t-butoxy-carbonyl)amino)propanamide

[0810]

[0811] TLC: Rf 0.71 (hexane:ethyl acetate=1:1).

Example 2(112)(2R)-N-(4-benzyloxybenzyl)-2-t-butoxycarbonylamino-3-cyclohexyl-methylthiopropanamide

[0812]

[0813] TLC: Rf 0.54 (ethyl acetate:hexane=1:2);

[0814] NMR (CDCl₃): δ 7.46-7.15 (m, 7H), 6.98-6.88 (m, 2H), 6.64 (t,J=6.0 Hz, 1H), 5.35 (d, J=6.6 Hz, 1H), 5.05 (s, 2H), 4.39 (d, J=5.4 Hz,2H), 4.28-4.18 (m, 1H), 2.98 (dd, J=3.8, 5.8 Hz, 1H), 2.82 (dd, J=13.8,7.0 Hz, 1H), 2.42 (d, J=7.8 Hz, 2H), 1.88-0.76 (m, 20H).

Example 2(113)(2R)-N-(3-benzyloxy-4-methoxybenzyl)-2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide

[0815]

[0816] TLC: Rf 0.33 (hexane:ethyl acetate=2:1);

[0817] NMR (CDCl₃): δ 7.47-7.30 (m, 5H), 6.86-6.84 (m, 3H), 6.60 (t,J=6.0 Hz, 1H) 5.31 (d, J=6.8 Hz, 1H), 5.14 (s, 2H), 4.35 (d, J=6.0 Hz,2H), 4.26-4.16 (m, 1H), 3.87 (s, 3H), 2.96 (dd, J=13.6, 5.6 Hz, 1H),2.80 (dd, J=13.6, 6.6 Hz, 1H), 2.50-2.34 (m, 2H), 1.85-1.57 (m, 5H),1.53-1.35 (m, 10H), 1.33-0.78 (m, 5H).

Example 2(114)N-((1R)-2-cyclohexylmethylthio-1-(4-phenylpiperazin-1-ylcarbonyl)ethyl)-carbamideacid.t-butyl ester

[0818]

[0819] TLC: Rf 0.49 (ethyl acetate:hexane=1:2);

[0820] NMR (CDCl₃): δ 7.33-7.25 (m, 2H), 6.95-6.89 (m, 3H), 5.41 (d,J=8.7 Hz, 1H), 4.86-4.78 (m, 1H), 3.82-3.76 (m, 4H), 3.26-3.17 (m, 4H),2.87 (dd, J=13.5, 7.5 Hz, 1H), 2.76 (dd, J=13.5, 6.0 Hz, 1H), 2.44 (d,J=6.9 Hz, 2H), 1.84-0.86 (m, 20H).

Example 2(115)(2R)-N-(2-phenoxypyridin-5-yl)-2-t-butoxycarbonylamino-3-cyclohexyl-methylthiopropanamide

[0821]

[0822] TLC: Rf 0.56 (ethyl acetate:hexane=1:2);

[0823] NMR (CDCl₃): δ 8.53 (br. s, 1H), 8.20 (d, J=3.0 Hz, 1H), 8.07(dd, J=9.0, 2.8 Hz, 1H), 7.44-7.34 (m, 2H), 7.22-7.09 (m, 3H), 6.89 (d,J=9.2 Hz, 1H), 5.47 (d, J=7.2 Hz, 1H), 4.42-4.32 (m, 1H), 3.04 (dd,J=13.8, 6.2 Hz, 1H), 2.88 (dd, J=13.8, 7.0 Hz, 1H), 2.48 (d, J=6.6 Hz,2H), 1.90-0.79 (m, 20H).

Example 2(116)(2R)-N-(2-phenoxypyridin-5-ylmethyl)-2-t-butoxycarbonylamino-3-cyclohexyl-methylthiopropanamide

[0824]

[0825] TLC: Rf 0.59 (ethyl acetate:hexane=1:1);

[0826] NMR (CDCl₃): δ 8.11-8.07 (m, 1H), 7.66 (dd, J=8.4, 2.2 Hz, 1H),7.46-7.35 (m, 2H), 7.25-7.08 (m, 4H), 6.87 (d, J=8.4 Hz, 1H), 6.82-6.74(m, 1H), 5.34 (d, J=7.2 Hz, 1H), 4.42 (d, J=6.4 Hz, 2H), 4.29-4.19 (m,1H), 2.97 (dd, J=13.6, 5.6 Hz, 1H), 2.82 (dd, J=13.6, 6.6 Hz, 1H), 2.42(d, J=6.6 Hz, 2H), 1.88-0.78 (m, 20H).

Example 2(117)(2R)-N-(4-(morpholin-4-yl)benzyl)-2-t-butoxycarbonylamino-3-cyclohexyl-methylthiopropanamide

[0827]

[0828] TLC: Rf 0.41 (ethyl acetate:hexane=1:1);

[0829] NMR (CDCl₃): δ 7.23-7.18 (m, 2H), 6.89-6.84 (m, 2H), 6.60 (t,J=5.1 Hz, 1H), 5.35 (d, J=7.8 Hz, 1H), 4.38 (d, J=5.7 Hz, 2H), 4.26-4.20(m, 1H), 3.88-3.84 (m, 4H), 3.16-3.12 (m, 4H), 2.98 (dd, J=13.8, 5.7 Hz,1H), 2.82 (dd, J=13.8, 6.9 Hz, 1H), 2.45 (dd, J=12.6, 6.6 Hz, 1H), 2.40(dd, J=12.6, 6.9 Hz, 1H), 1.85-0.82 (m, 20H).

Example 2(118)(2R)-N-(1-phenylpiperidin-4-yl)-2-t-butoxycarbonylamino-3-cyclohexyl-methylthiopropanamide

[0830]

[0831] TLC: Rf 0.42 (hexane:ethyl acetate=2:1);

[0832] NMR (CDCl₃): δ 7.29-7.22 (m, 2K), 6.95-6.92 (m, 2H), 6.88-6.82(m, 1H), 6.37 (d, J=7.5 Hz, 1H), 5.36 (d, J=6.6 Hz, 1H), 4.20-4.13 (m,1H), 4.01-3.88 (m, 1H), 3.63-3.56 (m, 2K), 2.99-2.86 (m, 3H), 2.78 (dd,J=13.5, 6.9 Hz, 1H), 2.48 (dd, J=12.6, 6.9 Hz, 1H), 2.45 (dd, J=12.6,6.6 Hz, 1H), 2.08-1.98 (m, 2H), 1.87-1.78 (br, 2H), 1.76-1.54 (m, 5K),1.52-1.38 (m, 100H), 1.31-1.06 (m, 3K), 1.00-0.86 (m, 2K).

Example 2(119)(2R)-N-(1-methylpiperidin-4-yl)-2-t-butoxycarbonylamino-3-cyclohexyl-methylthiopropanamide

[0833]

[0834] TLC: Rf 0.41 (chloroform:methanol=9:1);

[0835] NMR (CDCl₃): δ 6.41 (d, J=6.9 Hz, 1H), 5.36 (d, J=6.6 Hz, 1H),4.19-4.12 (m, 1H), 3.88-3.75 (m, 1H), 2.97-2.75 (m, 4H), 2.51-2.40 (m,2H), 2.36 (s, 3H), 2.31-2.21 (m, 2H), 1.99-1.88 (m, 2H), 1.86-1.56 (m,7H), 1.53-1.59 (m, 10H), 1.30-0.86 (m, 5H).

Example 3˜Example 3(1)

[0836] By the same desired procedure as Reference Example 3, using thecompounds prepared in Example 2(64) and Example 2(65), the followingcompounds of the present invention were obtained.

Example 3(2S)-N-((1S)-1-carboxy-2-phenylethyl)-3-cyclohexyloxycarbonyl-2-t-butoxy-carbonylaminopropanamide

[0837]

[0838] TLC: Rf 0.51 (chloroform:methanol=9:1);

[0839] NMR (CDCl₃): δ 7.35-7.17 (5H, m), 7.04 (1H, d, J=7.8 Hz),6.90-6.10 (1H, br. s), 5.64 (1H, d, J=8.0 Hz), 4.86-4.69 (2H, m),4.61-4.42 (1H, m), 3.18 (1H, dd, J=13.8, 5.4 Hz), 3.07 (1H, dd, J=13.8,6.2 Hz), 2.86 (1H, dd, J=17.0, 5.0 Hz), 2.64 (1H, dd, J=17.0, 6.2 Hz),1.88-1.18 (19H, m).

Example 3(1)(2S)-N-((1S)-1-carboxyethyl)-3-cyclohexyloxycarbonyl-2-t-butoxycarbonyl-aminopropanamide

[0840]

[0841] TLC: Rf 0.46 (chloroform:methanol=9:1);

[0842] NMR (CDCl₃): δ 7.20 (1H, d, J=6.0 Hz), 6.50-6.00 (1H, br. s),5.74 (1H, d, J=8.4 Hz), 4.85-4.69 (1H, m), 4.66-4.47 (2H, m), 2.93 (1H,dd, J=17.0, 5.2 Hz), 2.69 (1H, dd, J=17.0, 6.0 Hz), 1.92-1.20 (22H, m).

Example 4˜Example 4(1)

[0843] By the reaction of the compounds prepared in Example 3 andExample 3(1) with alcohol derivatives by the same desired procedure asExample 2, the following compounds of the present invention wereobtained.

Example 4(2S)-N-((1S)-1-(4-methoxybenzyloxycarbonyl)ethyl)-3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanamide

[0844]

[0845] TLC:Rf 0.34 (ethyl acetate:hexane=1:2)

[0846] NMR (CDCl₃): δ 7.31-7.24 (2H, m), 7.07 (1H, d, J=7.0 Hz),6.92-6.85 (2H, m), 5.66 (1H, d, J=8.2 Hz), 5.13 (1H, d, J=12.2 Hz), 5.06(11H, d, J=12.2 Hz), 4.84-4.70 (1H, m), 4.62-4.46 (2H, m), 3.81 (3H, s),2.96 (1H, dd, J=16.8, 4.4 Hz), 2.64 (1H, dd, J=16.8, 6.4 Hz), 1.92-1.24(22H, m).

Example 4(l)(2S)-N-((1S)-2-phenyl-1-(4-methoxybenzyloxycarbonyl)ethyl)-3-cyclohexyl-oxycarbonyl-2-t-butoxycarbonylaminopropanamide

[0847]

[0848] TLC: Rf 0.42 (ethyl acetate:hexane=1:2);

[0849] NMR (CDCl₃): δ 7.26-7.19 (5H, m), 7.06-7.01 (2H, m), 6.97 (1H, d,J=8. OHz), 6.91-6.84 (2H, m), 5.61 (1H, d, J=7.8 Hz), 5.09 (1H, d,J=12.0 Hz), 5.01 (1H, d, J=12.0 Hz), 4.86-4.69 (2H, m), 4.56-4.40 (1H,m), 3.82 (3H, s), 3.08 (1H, d, J=5.8 Hz), 2.93 (1H, dd, J=17.0, 4.4 Hz),2.62 (1H, dd, J=17.0, 6.2 Hz), 1.90-1.18 (19H, m).

Reference Example 4 (2lS)-N-(4-methoxybenzyl)-3-cyclohexylmethoxy-2-aminopropanamide.hydrochloride

[0850]

[0851] Under cooling with ice, a solution of 4N solution of hydrogenchloride in dioxane (12 ml) was added dropwise to the compound preparedin Example 2 (1180 mg). The solution was warmed to room temperature andstirred for 1 hour. The reaction mixture was concentrated to give thetitle compound (920 mg) having the following physical data.

[0852] TLC: Rf 0.78 (chloroform:methanol=9:1);

[0853] NMR (CD₃OD): δ 7.26-7.19 (2H, m), 6.91-6.83 (2H, m), 4.43 (1H, d,J=14.6 Hz), 4.28 (1H, d, J=14.6 Hz), 4.03 (1H, dd, J=5.8, 4.0 Hz),3.83-3.66 (5H, m), 3.35-3.20 (2H, m), 1.75-0.81 (11H, m).

Example 5(2S)-N-(4-methoxybenzyl)-3-cyclohexylmethoxy-2-benzoylaminoprpanamide

[0854]

[0855] Benzoyl chloride (0.04 ml) was added dropwise to a solution ofthe compound prepared in Reference Example 4 (95 mg) and pyridine (0.07ml) in methylene chloride (2 ml). The mixture was stirred for 1 hour atroom temperature. The reaction mixture was diluted with methylenechloride and washed with 1N hydrochloric acid, water and saturatedaqueous sodium chloride, successively, dried over anhydrous magnesiumsulfate. The organic layer was concentrated and the residue was purifiedby silica gel column chromatography (hexane:ethyl acetate=2:1) to givethe compound of the present invention (90 mg) having the followingphysical data.

[0856] TLC: Rf 0.21 (ethyl acetate:hexane=1:2);

[0857] NMR (CDCl₃): δ 7.86-7.80 (2H, m), 7.56-7.39 (3H, m), 7.27-7.18(3H, m), 6.93-6.83 (3H, m), 4.70 (1H, ddd, J=8.8, 6.4, 4.2 Hz), 4.47(1H, dd, J=14.8, 5.6 Hz), 4.39 (1H, dd, J=14.8, 5.6 Hz), 3.95 (1H, dd,J=9.0, 4.2 Hz), 3.80 (3H, s), 3.50 (1H, t, J=8.4 Hz), 3.36 (1H, dd,J=9.0, 6.2 Hz), 3.24 (1H, dd, J=9.0, 6.2 Hz), 1.77-0.71 (11H, m).

Example 6˜Example 6(86)

[0858] By the same desired procedure as Reference Example 4→Example 5,using the compounds prepared in Example 2, Example 2(4), Example 2(9),Example 2(80), Example 2(83), Example 2(100)˜Example 2(119), Example 3and Example 3(1), the following compounds of the present invention wereobtained.

[0859] Also, (−)-3-t-butoxycarbonylthiazolidin-2-ylcarboxylic acid wasused for the preparation of the compound of Example 6(60).

[0860] (+)-3-t-butoxycarbonylthiazolidin-2-ylcarboxylic acid was usedfor the preparation of the compound of Example 6(61).

[0861] (+)-3-t-butoxycarbonylthiazolidin-2-ylcarboxylic acid was usedfor the preparation of the compound of Example 6(63).

Example 6 (2S)-3-cyclopentyloxycarbonyl-2-methylcarbonylaminopropanoicacid.4-methoxybenzyl ester

[0862]

[0863] TLC: Rf 0.27 (ethyl acetate:hexane=1:1)

[0864] NMR (CDCl₃): δ 7.29-7.23 (2H, m), 6.92-6.84 (2H, m), 6.50 (1H,br. d, J=7.0 Hz), 5.19-5.05 (3H, m), 4.88-4.80 (1H, m), 3.81 (3H, s),2.97 (1H, dd, J=17.2, 4.4 Hz), 2.78 (1H, dd, J=17.2, 4.4 Hz), 2.02 (3H,s), 1.92-1.46 (8H, m).

Example 6(1) (2S)-3-cyclopentyloxycarbonyl-2-benzoylaminopropanoicacid.4-methoxybenzyl ester

[0865]

[0866] TLC: Rf 0.54 (ethyl acetate:hexane=1:1);

[0867] NMR (CDCl₃): δ 7.82-7.77 (2H, m), 7.56-7.38 (3H, m), 7.32-7.21(3H, m), 6.91-6.84 (2H, m), 5.18-5.01 (4H, m), 3.81 (3H, s), 3.08 (1H,dd, J=17.0, 4.2 Hz), 2.91 (1H, dd, J=17.0, 4.6 Hz), 1.92-1.49 (8H, m).

Example 6(2) (2S)-3-cyclopentyloxycarbonyl-2-pivalocyaminopropanoicacid.4-methoxybenzyl ester

[0868]

[0869] TLC: Rf 0.53 (ethyl acetate:hexane=1:1);

[0870] NMR (CDCl₃): δ 7.29-7.23 (2H, m), 6.91-6.85 (2H, m), 6.71 (1H,br. d, J=8.2 Hz), 5.18-5.04 (3H, m), 4.86-4.77 (1H, m), 3.81 (3H, s),2.98 (1H, dd, J=17.2, 4.4 Hz), 2.77 (1H, dd, J=17.2, 4.4 Hz), 1.94-1.45(8H, m), 1.19(9H, s).

Example 6(3) (2S)-3-cyclopentyloxycarbonyl-2-cinnamoylaminopropanoicacid.4-methoxybenzyl ester

[0871]

[0872] TLC: Rf 0.56 (ethyl acetate:hexane=1:1);

[0873] NMR (CDCl₃). 7.63 (1H, d, J=15.6 Hz), 7.53-7.46 (2H, m),7.40-7.33 (3H, m), 7.32-7.25 (2H, m), 6.92-6.84 (2H, m), 6.68 (1H, br.d, J=8.0 Hz), 6.44 (1H, d, J=15.6 Hz), 5.22-5.08 (3H, m), 5.03-4.94 (1H,m), 3.80 (3H, s), 3.05 (1H, dd, J=17.4, 4.4 Hz), 2.87 (1H, dd, J=17.4,4.4 Hz), 1.93-1.44 (8H, m).

Example 6(4) (2S)-3-cyclopentyloxycarbonyl-2-valerylaminopropanoicacid.4-methoxybenzyl ester

[0874]

[0875] TLC: Rf 0.50 (ethyl acetate:hexane=1:1);

[0876] NMR (CDCl₃): δ 7.30-7.23 (2H, m), 6.92-6.84 (2H, m), 6.47 (1H, d,J=8.3 Hz), 5.16 (1H, d, J=12.0 Hz), 5.08 (1H, d, J=12.0 Hz), 4.90-4.81(1H, m), 3.81 (3H, s), 2.98 (1H, dd, J=17.0, 4.3 Hz), 2.77 (1H, dd,J=17.0, 4.5 Hz), 2.22 (2H, t, J=7.4 Hz), 1.92-1.46 (10H, m), 1.42-1.24(2H, m), 0.98 (3H, t, J=8.0 Hz).

Example 6(5)(2S)-3-cyclopentyloxycarbonyl-2-(octylcarbonylamino)propanoicacid.4-methoxybenzyl ester

[0877]

[0878] TLC: Rf 0.62 (ethyl acetate:hexane=11);

[0879] NMR (CDCl₃): δ 7.30-7.23 (2H, m), 6.91-6.84 (2H, m), 6.46 (1H, d,J=7.6 Hz), 5.18-5.04 (3H, m), 4.89-4.81 (1H, m), 3.81 (3H, s), 2.98 (1H,dd, J=17.2, 4.2 Hz), 2.77 (1H, dd, J=17.2, 4.4 Hz), 2.21 (2H, t, J=7.0Hz), 1.92-1.46 (8H, m), 1.38-1.15 (12H, m), 0.88 (3H, t, J=7.2 Hz).

Example 6(6) (2S)-3-cyclopentyloxycarbonyl-2-mesylaminopropanoicacid.4-methoxybenzyl ester

[0880]

[0881] TLC: Rf 0.54 (ethyl acetate:hexane=1:1);

[0882] NMR (CDCl₃): δ 7.31-7.24 (2H, m), 6.92-6.85 (2H, m), 5.48 (1H, d,J=9.2 Hz), 5.22-5.05 (3H, m), 4.41-4.32 (1H, m), 3.81 (3H, s), 3.00 (1H,dd, J=17.4, 4.6 Hz), 2.99 (3H, s), 2.80 (1H, dd, J=17.4, 4.4 Hz),1.94-1.46 (8H, m).

Example 6(7)(2S)-3-cyclopentyloxycarbonyl-2-phenylsulfonylaminopropanoicacid.4-methoxybenzyl ester

[0883]

[0884] TLC: Rf 0.69 (ethyl acetate:hexane=1:1);

[0885] NMR (CDCl₃): δ 7.87-7.82 (2H, m), 7.60-7.41 (3H, m), 7.16-7.10(2H, m), 6.89-6.81 (2H, m), 5.69 (1H, d, J=8.3 Hz), 5.13-5.03 (1H, m),4.94 (3H, s), 4.21-4.12 (1H, m), 3.81 (3H, s), 2.92 (1H, dd, J=17.0, 4.3Hz), 2.77 (1H, dd, J=17.0, 4.8 Hz), 1.93-1.44 (8H, m).

Example 6(8)(2S)-3-cyclopentyloxycarbonyl-2-(butylsulfonylamino)propanoicacid.4-methoxybenzyl ester

[0886]

[0887] TLC: Rf 0.60 (ethyl acetate:hexane=1:2);

[0888] NMR (CDCl₃): δ 7.31-7.22 (2H, m), 6.92-6.83 (2H, m), 5.36 (1H, d,J=9.0 Hz), 5.21-5.05 (3H, m), 4.39-4.30 (1H, m), 3.79 (3H, s), 3.06-2.93(3H, m), 2.79 (1H, dd, J=17.2, 4.4 Hz), 1.92-1.24 (12H, m), 0.91 (3H, t,J=7.2 Hz).

Example 6(9)(2S)-3-cyclopentyloxycarbonyl-2-(octylsulfonylamino)propanoicacid.4-methoxybenzyl ester

[0889]

[0890] TLC: Rf 0.55 (ethyl acetate:hexane=1:2);

[0891] NMR (CDCl₃): δ 7.31-7.23 (2H, m), 6.92-6.73 (2H, m), 6.88 (2H, d,J=8.8 Hz), 5.35 (1H, d, J=10.0 Hz), 5.21-5.05 (3H, m), 4.39-4.30 (1H,m), 3.81 (3H, s), 3.03-2.93 (3H, m), 2.79 (1H, dd, J=17.2, 4.4 Hz),1.87-1.27 (20H, m), 0.89 (3H, t, J=6.8 Hz).

Example 6(10)(2S)-3-cyclopentyloxycarbonyl-2-((E)-styrylsulfonylamino)propanoicacid.4-methoxybenzyl ester

[0892]

[0893] TLC: Rf 0.38 (ethyl acetate:hexane=1:2);

[0894] NMR (CDCl₃): δ 7.49-7.41 (6H, m), 7.17 (2H, d, J=8.8 Hz),6.82-6.71 (3H, m), 5.55 (1H, d, J=8.6 Hz), 5.15-5.00 (3H, m), 4.26-4.17(1H, m), 3.78 (3H, s), 3.01 (1H, dd, J=17.2, 4.4 Hz), 2.84 (1H, dd,J=17.2, 4.4 Hz), 1.89-1.44 (8H, m).

Example 6(11)(2S)-3-cyclopentyloxycarbonyl-2-benzyloxycarbonylaminopropanoicacid.4-methoxybenzyl ester

[0895]

[0896] TLC: Rf 0.67 (ethyl acetate:hexane=1:2);

[0897] NMR (CDCl₃): δ 7.39-7.23 (7H, m), 6.91-6.82 (2H, m), 5.74 (1H, d,J=9.2 Hz), 5.17-5.04 (5H, m), 4.67-4.58 (1H, m), 3.80 (3H, s), 2.97 (1H,dd, J=17.0, 4.6 Hz), 2.78 (1H, dd, J=17.0, 4.8 Hz), 1.88-1.46 (8H, m).

Example 6(12) (2S)-3-cyclohexyloxycarbonyl-2-benzoylaminopropanoicacid.4-methoxybenzyl ester

[0898]

[0899] TLC: Rf 0.42 (ethyl acetate:hexane=1; 2);

[0900] NMR (CDCl₃): δ 7.83-7.76 (2H, m), 7.52-7.39 (3H, m), 7.32-7.21(3H, m), 6.91-6.83 (2H, m), 5.21 (1H, d, J=12.0 Hz), 5.11 (1H, d, J=12.0Hz), 5.10-5.02 (1H, m), 4.77-4.64 (1H, m), 3.81 (3H, s), 3.11 (1H, dd,J=17.0, 4.2 Hz), 2.93 (1H, dd, J=17.0, 4.6 Hz), 1.84-1.16 (10H, m).

Example 6(13)(2S)-3-cyclohexyloxycarbonyl-2-(4-fluorobenzoylamino)propanoicacid.4-methoxybenzyl ester

[0901]

[0902] TLC: Rf 0.37 (ethyl acetate:hexane=1:2);

[0903] NMR (CDCl₃): δ 7.86-7.76 (2H, m), 7.32-7.06 (5H, m), 6.91-6.84(2H, m), 5.20 (1H, d, J=1.8 Hz), 5.11 (1H, d, J=11.8 Hz), 5.08-4.99 (1H,m), 4.77-4.63 (1H, m), 3.81 (3H, m), 3.10 (1H, dd, J=17.2, 5.0 Hz), 2.91(1H, dd, J=17.2, 5.0 Hz), 1.84-1.13 (10H, m).

Example 6(14) (2S)-3-cyclohexyloxycarbonyl-2-(4-methoxybenzoyl)propanoicacid.4-methoxybenzyl ester

[0904]

[0905] TLC: Rf 0.32 (ethyl acetate:hexane=1:2);

[0906] NMR (CDCl₃): δ 7.80-7.73 (2H, m), 7.31-7.15 (2H, m), 7.13 (1H, d,J=7.8 Hz), 6.96-6.85 (4H, m), 5.20 (1H, d, J=12.0 Hz), 5.13 (1H, d,J=12.0 Hz), 5.08-5.00 (1H, m), 4.77-4.63 (1H, m), 3.85 (3H, s), 3.81(3H, s), 3.09 (1H, dd, J=17.2, 4.4 Hz), 2.91 (1H, dd, J=17.2, 4.4 Hz),1.84-1.09 (10H, m).

Example 6(15)(2S)-3-cyclohexyloxycarbonyl-2-(4-phenylbenzoylamino)propanoicacid.4-methoxybenzyl ester

[0907]

[0908] TLC: Rf 0.42 (ethyl acetate:hexane=1:2);

[0909] NMR (CDCl₃): δ 7.91-7.84 (2H, m), 7.69-7.58 (4H, m), 7.52-7.25(6H, m), 6.92-6.85 (2H, m), 5.22 (1H, d, J=12.0 Hz), 5.11 (1H, d, J=12.0Hz), 5.13-5.04 (1H, m), 4.80-4.64 (1H, m), 3.81 (3H, s), 3.12 (1H, dd,J=17.2, 4.2 Hz), 2.94 (1H, dd, J=17.2, 4.6 Hz), 1.84-1.14 (10H, m).

Example 6(16)(2S)-3-cyclohexyloxycarbonyl-2-(4-nitrobenzoylamino)propanoicacid.4-methoxybenzyl ester

[0910]

[0911] TLC: Rf 0.36 (ethyl acetate:hexane=1:2);

[0912] NMR (CDCl₃): δ 8.32-8.26 (2H, m), 7.99-7.92 (2H, m), 7.36 (1H,br. d, J=7.8 Hz), 7.32-7.25 (2H, m), 6.92-6.85 (2H, m), 5.22 (1H, d,J=12.0 Hz), 5.12 (1H, d, J=12.0 Hz), 5.08-5.00 (1H, m), 4.78-4.63 (1H,m), 3.81 (3H, s), 3.13 (1H, dd, J=17.2, 4.2 Hz), 2.93 (1H, dd, J=17.2,4.4 Hz), 1.84-1.14 (10H, m).

Example 6(17)(2S)-3-cyclohexyloxycarbonyl-2-(4-acetylbenzoylamino)propanoicacid.4-methoxybenzyl ester

[0913]

[0914] TLC: Rf 0.24 (ethyl acetate:hexane=1:2);

[0915] NMR (CDCl₃): δ 8.05-7.98 (2H, m), 7.90-7.85 (2H, m), 7.33-7.25(3H, m), 6.92-6.84 (2H, m), 5.21 (1H, d, J=11.8 Hz), 5.12 (1H, d, J=11.8Hz), 5.09-5.01 (1H, m), 4.78-4.64 (1H, m), 3.81 (3H, s), 3.12 (1H, dd,J=17.0, 4.2 Hz), 2.93 (1H, dd, J=17.0, 4.6 Hz), 2.64 (3H, s), 1.84-1.18(10H, m).

Example 6(18)(2S)-3-cyclohexyloxycarbonyl-2-(4-methylthiobenzoylamino)propanoicacid.4-methoxybenzyl ester

[0916]

[0917] TLC: Rf 0.37 (ethyl acetate:hexane=1:2);

[0918] NMR (CDCl₃): δ 7.75-7.68 (2H, m), 7.30-7.22 (4H, m), 7.18 (1H,br. d, J=7.8 Hz), 6.91-6.84 (2H, m), 5.20 (1H, d, J=11.8 Hz), 5.11 (1H,d, J=11.8 Hz), 5.08-5.00 (1H, m), 4.78-4.62 (1H, m), 3.81 (3H, s), 3.10(1H, dd, J=17.2, 4.4 Hz), 2.91 (1H, dd, J=17.2, 4.6 Hz), 2.51 (3H, s),1.84-1.12 (10H, m).

Example 6(19)(2S)-3-cyclohexyloxycarbonyl-2-(4-dimethylaminobenzoylamino)propanoicacid.4-methoxybenzyl ester

[0919]

[0920] TLC: Rf 0.24 (ethyl acetate:hexane=1:2);

[0921] NMR (CDCl₃): δ 7.74-7.66 (2H, m), 7.32-7.25 (2H, m), 7.04 (1H,br. d, J=7.4 Hz), 6.91-6.83 (2H, m), 6.69-6.63 (2H, m), 5.19 (1H, d,J=12.2 Hz), 5.11 (1H, d, J=12.2 Hz), 5.10-5.02 (1H, m), 4.78-4.64 (1H,m), 3.81 (3H, s), 3.09 (1H, dd, J=17.0, 4.4 Hz), 3.02 (6H, s) 2.91 (1H,dd, J=17.0, 4.6 Hz), 1.84-1.16 (10H, m).

Example 6(20)(2S)-N-((1S)-1-carboxyethyl)-3-cyclohexyloxycarbonyl-2-benzyloxycarbonyl-aminopopanamide

[0922]

[0923] TLC: Rf 0.48 (chloroform:methanol=8:2);

[0924] NMR (CDCl₃+CD₃OD): δ 7.52 (1H, d, J=6.2 Hz), 7.37-7.28 (5H, m),6.36 (1H, d, J=9.2 Hz), 5.15 (1H, d, J=12.2 Hz), 5.07 (1H, d, J=112.2Hz), 4.79-4.52 (2H, m), 4.42-4.29 (1H, m), 2.87 (1H, dd, J=16.8, 6.2Hz), 2.74 (1H, dd, J=16.8, 5.8 Hz), 1.82-1.08 (13H, m).

Example 6(21)(2S)-N-((1S)-2-phenyl-1-carboxyethyl)-3-cyclohexyloxycarbonyl-2-benzyloxycarbonylaminopropanamide.dicyclohexylaminesalt

[0925]

[0926] TLC: Rf 0.46 (chloroform:methanol=8:2)

[0927] NMR (CDCl₃+CD₃OD): δ 7.37-7.28 (5H, m), 7.19-7.12 (5H, m), 5.13(1H, d, J=12.0 Hz), 5.01 (1H, d, J=12.0 Hz), 4.79-4.64 (1H, m),4.61-4.40 (2H, m), 3.26-2.66 (6H, m), 2.06-1.08 (30H, m).

Example 6(22)(2S)-N-(4-methoxybenzyl)-3-cyclohexylmethoxy-2-phenylsulfonylamino-propanamide

[0928]

[0929] TLC: Rf 0.31 (ethyl acetate:hexane=1:2);

[0930] NMR (CDCl₃): δ 7.91-7.85 (2H, m), 7.66-7.48 (3H, m), 7.16-7.09(2H, m), 7.00-6.95 (1H, m), 6.88-6.80 (2H, m), 5.67-5.64 (1H, m), 4.36(1H, dd, J=14.6, 5.6 Hz), 4.27 (1H, dd, J=14.6, 5.4 Hz), 3.82-3.70 (5H,m), 3.29-3.21 (1H, m), 3.16 (1H, dd, J=9.0, 6.2 Hz), 3.04 (1H, dd,J=9.0, 6.6 Hz), 1.72-0.64 (11H, m).

Example 6(23)(2S)-N-(4-methoxybenzyl)-3-cyclohexylmethoxy-2-pivaloylaminopropanamide

[0931]

[0932] TLC: Rf 0.24 (ethyl acetate:hexane=1:2);

[0933] NMR (CDCl₃): δ 7.23-7.15 (2H, m), 6.89-6.77 (3H, m), 6.67 (1H, d,J=6.0 Hz), 4.50-4.29 (3H, m), 3.83-3.76 (4H, m), 3.43-3.16 (3H, m),1.72-0.71 (20H, m).

Example 6(24)(2S)-N-(4-methoxybenzyl)-3-cyclohexylmethoxy-2-(4-methoxybenzoylamino)-propanamide

[0934]

[0935] TLC: Rf 0.11 (ethyl acetate:hexane=1:2);

[0936] NMR (CDCl₃): δ 7.83-7.75 (2H, m), 7.25-7.17 (2H, m), 7.10 (1H, d,J=5.8 Hz), 6.97-6.82 (5H, m), 4.68 (1H, ddd, J=10.0, 5.8, 3.8 Hz), 4.42(2H, d, J=5.4 Hz), 3.95 (1H, dd, J=9.2, 4.0 Hz), 3.86 (3H, s), 3.80 (3H,s), 3.49 (1H, t, J=9.2 Hz), 3.36 (1H, dd, J=9.2, 6.2 Hz), 3.24 (1H, dd,J=9.2, 6.6 Hz), 1.76-0.74 (11H, m).

Example 6(25)(2S)-N-(4-methoxybenzyl)-3-cyclohexylmethoxy-2-(4-nitrobenzoylamino)-propanamide

[0937]

[0938] TLC: Rf 0.26 (ethyl acetate:hexane=1:2);

[0939] NMR (CDCl₃): δ 8.33-8.26 (2H, m), 8.01-7.94 (2H, m), 7.38 (1H, d,J=5.8 Hz), 7.25-7.18 (2H, m), 6.95-6.83 (3H, m), 4.67 (1H, ddd, J=9.6,5.8, 4.0 Hz), 4.48 (1H, dd, J-=14.6, 5.8 Hz), 4.38 (1H, dd, J=14.6, 5.4Hz), 3.92 (1H, dd, J=9.2, 4.4 Hz), 3.80 (3H, s), 3.49 (1H, t, J=9.2 Hz),3.37 (1H, dd, J=9.6, 6.2 Hz), 3.24 (1H, dd, J=9.6, 6.6 Hz), 1.74-0.70(11H, m).

Example 6(26)(2S)-N-(4-methoxybenzyl)-3-cyclohexylmethoxy-2-(12-methyltridecylcarbonyl-amino)propanamide

[0940]

[0941] TLC: Rf 0.60 (ethyl acetate:hexane=1:1);

[0942] NMR (CDCl₃): δ 7.23-7.15 (2H, m), 6.89-6.82 (2H, m), 6.81-6.70(1H, m), 6.41 (1H, d, J=6.2 Hz), 4.50 (1H, ddd, J=8.4, 6.6, 4.4 Hz),4.39 (2H, d, J=6.2 Hz), 3.86-3.73 (4H, m), 3.39 (1H, t, J=8.8 Hz), 3.30(1H, dd, J=9.4, 6.0 Hz), 3.19 (1H, dd, J=9.4, 6.2 Hz), 2.22 (1H, t,J=7.0 Hz), 1.74-0.70 (38H, m).

Example 6(27)(2S)-N-(4-methoxybenzyl)-3-cyclohexylmethoxy-2-cyclohexylcarbonylamino-propanamide

[0943]

[0944] TLC: Rf 0.48 (ethyl acetate:hexane=1:1);

[0945] NMR (CDCl₃): δ 7.22-7.15 (2H, m), 6.89-6.73 (3H, m), 6.43 (1H, d,J=6.4 Hz), 4.48 (1H, ddd, J=8.2, 6.4, 4.2 Hz), 4.46-4.29 (2H, m),3.82-3.73 (4H, m), 3.38 (1H, t, J=8.4 Hz), 3.31 (1H, dd, J=9.2, 6.4 Hz),3.20 (1H, dd, J=9.2, 6.2 Hz), 2.14 (1H, tt, J=11.6, 4.0 Hz), 1.94-0.71(21H, m).

Example 6(28)(2S)-N-(4-methoxybenzyl)-3-cyclohexylmethoxy-2-(4-methoxyphenylsulfonyl-amino)propanamide

[0946]

[0947] TLC: Rf 0.21 (ethyl acetate:hexane=1:2);

[0948] NMR (CDCl₃): δ 7.83-7.76 (2H, m), 7.16-7.09 (2H, m), 7.05-6.94(3H, m), 6.88-6.80 (2H, m), 5.55 (1H, d, J=5.4 Hz), 4.38 (1H, dd,J=14.6, 5.8 Hz), 4.28 (1H, dd, J=14.6, 5.6 Hz), 3.88 (3H, s), 3.82-3.67(5H, m), 3.26 (1H, dd, J=8.8, 6.4 Hz), 3.17 (1H, dd, J=9.2, 6.2 Hz),3.05 (1H, dd, J=9.2, 6.2 Hz), 1.74-0.79 (11H, m).

Example 6(29)(2S)-N-(4-methoxybenzyl)-3-cyclohexylmethoxy-2-cyclohexylsulfonylamino-propanamide

[0949]

[0950] TLC: Rf 0.24 (ethyl acetate:hexane=1:2);

[0951] NMR (CDCl₃): δ 7.23-7.16 (2H, m), 7.01 (1H, t, J=4.8 Hz),6.90-6.82 (2H, m), 5.23 (1H, d, J=6.6 Hz), 4.40 (2H, d, J=5.8 Hz),4.06-3.97 (1H, m), 3.85 (1H, dd, J=9.2, 4.0 Hz), 3.80 (3H, s), 3.55 (1H,dd, J=9.2, 7.2 Hz), 3.28 (1H, dd, J=9.2, 6.6 Hz), 3.20 (1H, dd, J=9.2,6.2 Hz), 2.90 (1H, tt, J=11.8, 3.2 Hz), 2.28-2.08 (2H, m), 1.93-1.82(2H, m), 1.76-1.04 (15H, m), 0.94-0.70 (2H, m).

Example 6(30)(2R)-N-(4-methoxybenzyl)3-cyclohexylmethylthio-2-cyclopentylcarbonyl-aminopropanamide

[0952]

[0953] TLC: Rf 0.19 (ethyl acetate:hexane=1:2);

[0954] NMR (CDCl₃): δ 7.24-7.05 (3H, m), 6.87-6.80 (2H, m), 6.59 (1H, d,J=7.0 Hz), 4.62-4.52 (1H, m), 4.39 (1H, dd, J=15.0, 5.8 Hz), 4.31 (1H,dd, J=15.0, 5.4 Hz), 3.78 (3H, s), 2.93 (1H, dd, J=13.4, 5.4 Hz), 2.79(1H, dd, J=13.4, 7.4 Hz), 2.66-2.50 (1H, m), 2.45 (2H, d, J=7.0 Hz),1.95-0.78 (19H, m).

Example 6(31)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-cyclohexylcarbonyl-aminopropanamide

[0955]

[0956] TLC: Rf 0.27 (ethyl acetate:hexane=1:2);

[0957] NMR (CDCl₃): δ 7.24-7.16 (2H, m), 6.89-6.78 (3H, m), 6.46 (1H, d,J=6.8 Hz), 4.52-4.42 (1H, m), 4.38 (2H, d, J=5.8 Hz), 3.79 (3H, S), 2.95(1H, dd, J=13.6, 5.0 Hz), 2.74 (1H, dd, J=13.6, 8.0 Hz), 2.47 (2H, d,J=7.0 Hz), 2.20-2.05 (1H, m), 1.92-0.82 (21H, m).

Example 6(32)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-cyclobutylcarbonylamino-propanamide

[0958]

[0959] TLC: Rf 0.15 (hexane:ethyl acetate=2:1)

[0960] NMR (CDCl₃): δ 7.20 (2H, d, J=8.6 Hz), 6.86 (2H, d, J=8.6 Hz),6.80-6.72 (1H, br), 6.35 (1H, d, J=7.0 Hz), 4.52-4.38 (3H, m), 3.80 (3H,s), 3.09-2.91 (2H, m), 2.73 (1H, dd, J=8.0, 14.0 Hz), 2.48 (2H, d, J=6.6Hz), 2.38-2.07 (4H, m), 2.06-1.32 (8H, m), 1.27-1.08 (3H, m), 1.03-0.89(2H, m).

Example 6(33)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-cycloheptylcarbonyl-aminopropanamide

[0961]

[0962] TLC: Rf 0.30 (hexane:ethyl acetate=2:1);

[0963] NMR (CDCl₃): δ 7.20 (2H, d, J-8.6 Hz), 6.86 (2H, d, J=8.6 Hz),6.80-6.74 (1H, br), 6.37 (1H, d, J=7.0 Hz), 4.50-4.37 (3H, m), 3.80 (3H,s), 2.95 (1H, dd, J=5.6, 14.0 Hz), 2.74 (1H, dd, J-8.0,14.0 Hz), 2.47(2H, d, J=6.6 Hz), 2.35-2.20 (11H, m), 1.95-1.33 (18H, m), 1.30-1.08(3H, m), 1.03-0.90 (2H, m).

Example 6(34)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(4-methoxycyclohexyl-carbonylamino)propanamide

[0964]

[0965] (The relative configuration of cyclohexyl ring substituted bymethoxy group is not determined, but the above compound is a singlecompound. This compound is the isomer of the compound prepared inExample 6(35).) less polar

[0966] TLC: Rf 0.46 (hexane:ethyl acetate=1:1);

[0967] NMR (CDCl₃): δ 7.20 (2H, d, J=8.8 Hz), 6.86 (2H, d, J=8.8 Hz),6.82-6.79 (1H, br), 6.49 (1H, d, J=7.0 Hz), 4.51-4.37 (3H, m), 3.80 (3H,s), 3.46-3.39 (1H, m), 3.29 (3H, s), 2.95 (1H, dd, J=5.6, 14.0 Hz), 2.73(1H, dd, J=8.0, 14.0 Hz), 2.47 (2H, d, J=6.6 Hz), 2.28-2.13 (1H, m),2.00-1.59 (12H, m), 1.51-0.93 (7H, m).

Example 6(35)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(4-methoxycyclohexyl-carbonylamino)propanamide

[0968]

[0969] (The relative configuration of cyclohexyl ring substituted bymethoxy group is not determined, but the above compound is a singlecompound. This compound is the isomer of the compound prepared inExample 6(34).) more polar

[0970] TLC: Rf 0.33 (hexane:ethyl acetate=1:1);

[0971] NMR (CDCl₃): δ 7.20 (2H, d, J=8.8 Hz), 6.86 (2H, d, J=8.8 Hz),6.77 (1H, t, J=5.8 Hz), 6.48 (1H, d, J=7.0 Hz), 4.50-4.37 (3H, m), 3.80(3H, s), 3.35 (3H, s), 3.12 (1H, tt, J=4.2, 10.6 Hz), 2.94 (1H, dd,J=5.1, 13.9 Hz), 2.72 (1H, dd, J=8.1, 13.9 Hz), 2.47 (2H, d, J=6.6 Hz),2.17-2.03 (3H, m), 2.00-1.57 (8H, m), 1.51-0.93 (9H, m).

Example 6(36)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((2RS)-3-t-butoxy-carbonylthiazolidin-2-ylcarbonylamino)propanamide

[0972]

[0973] TLC: Rf 0.29 (ethyl acetate:hexane=2:3);

[0974] NMR (CD₃OD): δ 7.23 (2H, d, J=9 Hz), 6.85 (2H, d, J=9 Hz), 5.23(1H, bs), 4.56-4.44 (1H, m), 4.44-4.22 (2H, m), 4.00-3.84 (1H, m),3.81-3.63 (1H, m), 3.77 (3H, s), 3.40-2.65 (4H, m), 2.42 (2H, d, J=7Hz), 1.91-1.58 (6H, m), 1.58-1.10 (3H, m), 1.45 and 1.40 (9H, s),1.05-0.80 (2H, m).

Example 6(37)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(2-methylpropylcarbonyl-amino)propanamide

[0975]

[0976] TLC: Rf 0.36 (ethyl acetate:hexane=2:3)

[0977] NMR (CD₃OD): δ 7.26-7.16 (2H, m), 6.91-6.76 (3H, m), 6.43 (1H, d,J=8 Hz), 4.50 (1H, td, J=8, 5 Hz), 4.38 (2H, d, J=6 Hz), 3.80 (3H, s),2.95 (1H, dd, J=14, 6 Hz), 2.76 (1H, dd, J=14, 8 Hz), 2.47 (2H, d, J=7Hz), 2.20-1.95 (3H, m), 1.89-1.56 (6H, m), 1.56-1.05 (3H, m), 1.05-0.78(2H, m), 0.94 (3H, d, J=7 Hz), 0.93 (3H, d, J=7 Hz).

Example 6(38)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(2-methylpropyloxy-carbonylamino)propanamide

[0978]

[0979] TLC: Rf 0.53 (ethyl acetate:hexane=2:3);

[0980] NMR (CDCl₃): δ 7.26-7.15 (2H, m), 6.92-6.80 (2H, m), 6.75-6.58(1H, m), 5.58 (1H, d, J=8 Hz), 4.40 (2H, d, J=6 Hz), 4.27 (1H, td, J=8,5 Hz), 3.85 (2H, d, J=7 Hz), 3.80 (3H, s), 2.99 (1H, dd, J=14, 5 Hz),2.82 (1H, dd, J=14, 8 Hz), 2.44 (2H, d, J=7 Hz), 2.02-1.55 (6H, m),1.55-1.03 (4H, m), 1.03-0.77 (2H, m), 0.92 (6H, d, J=7 Hz).

Example 6(39)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(1-(t-butoxycarbonyl)-piperidin-4-ylcarbonylamino)propanamide

[0981]

[0982] TLC: Rf 0.17 (hexane:ethyl acetate=2:1);

[0983] NMR (CDCl₃): δ 7.20 (2H, d, J=8.2 Hz), 6.87 (2H, d, J=8.2 Hz),6.79-6.73 (1H, br), 6.54 (1H, d, J=7.2 Hz), 4.50-4.38 (3H, m), 4.16-4.10(2H, br), 3.80 (3H, s), 2.93 (1H, dd, J=4.9, 13.7 Hz), 2.81-2.67 (3H,m), 2.48 (2H, d, J=7.0 Hz), 2.29 (1H, tt, J=4.0, 11.8 Hz), 1.83-1.57(9H, m), 1.46 (9H, s), 1.36-0.84 (6H, m).

Example 6(40)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(4-(t-butoxycarbonyl-amino)cyclohexylcarbonylamino)propanamide

[0984]

[0985] (The relative configuration of cyclohexyl ring substituted byt-butoxycarbonylamino group is not determined, but the above compound isa single compound. This compound is the isomer of the compound preparedin Example 6(41).)

[0986] TLC: Rf 0.27 (hexane:ethyl acetate=1:1);

[0987] NMR (CDCl₃): δ 7.20 (2H, d, J=8.8 Hz), 6.94-6.82 (3H, m), 6.61(1H, d, J=6.8 Hz), 4.71 (1H, d, J=8.0 Hz), 4.54-4.44 (1H, m), 4.38 (2H,d, J=5.4 Hz), 3.79-3.65 (4H, m), 2.92 (1H, dd, J=5.4, 13.8 Hz), 2.75(1H, dd, J=8.0, 13.8 Hz), 2.47 (2H, d, J=6.6 Hz), 2.30-2.15 (1H, br),1.92-1.53 (13H, m), 1.44 (9H, s), 1.26-1.08 (4H, m), 1.00-0.83 (2H, m).

Example 6(41)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(4-(t-butoxycarbonyl-amino)cyclohexylcarbonylamino)propanamide

[0988]

[0989] (The relative configuration of cyclohexyl ring substituted byt-butoxycarbonylamino group is not determined, but the above compound isa single compound. This compound is the isomer of the compound preparedin Example 6(40).)

[0990] TLC: Rf 0.27 (hexane:ethyl acetate=1:1);

[0991] NMR (CDCl₃): δ 7.20 (2H, d, J=8.8 Hz), 6.86 (2H, d, J=8.8 Hz),6.78-6.73 (1H, br), 6.48 (1H, d, J=6.6 Hz), 4.49-4.37 (4H, m), 3.80 (3H,s), 3.51-3.30 (1H, br), 2.93 (1H, dd, J=5.1, 13.9 Hz), 2.72 (1H, dd,J=8.1, 13.9 Hz), 2.48 (2H, d, J=6.6 Hz), 2.14-1.53 (14H, m), 1.44 (9H,s), 1.27-1.07 (4H, m), 1.00-0.83 (2H, m).

Example 6(42)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(tetrahydrofuran-2-ylcarbonylamino)propanamide

[0992]

[0993] TLC: Rf 0.27 (hexane:ethyl acetate=2:1);

[0994] NMR (DMSO-d₆): δ 7.43 (1H, t, J=10.6 Hz), 7.20 (2H, d, J=8.8 Hz),6.85 (2H, d, J=8.8 Hz), 6.80-6.71 (1H, br), 4.55-4.31 (4H, m), 4.05-3.83(2H, m), 3.79 (3H, s), 3.00-2.74 (2H, m), 2.45 (2H, t, J=6.6 Hz),2.36-1.62 (9H, m), 1.51-1.07 (4H, m), 1.03-0.90 (2H, m).

Example 6(43)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethoxy-2-cyclohexylcarbonyl-aminopropanamide

[0995]

[0996] TLC: Rf 0.31 (ethyl acetate:hexane=2:3);

[0997] NMR (CDCl₃): δ 7.25-7.14 (2H, m), 6.93-6.72 (3H, m), 6.43 (1H, d,J=6 Hz), 4.49 (1H, ddd, J=8, 6, 4 Hz), 4.43-4.28 (2H, m), 3.84-3.73 (1H,m), 3.80 (3H, s), 3.45-3.33 (1H, m), 3.29 (1H, dd, J=9, 5 Hz), 3.21 (1H,dd, J=9, 6 Hz), 2.24-2.06 (1H, m), 1.95-0.70 (21H, m).

Example 6(44)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-t-butoxycarbonyl-thiazolidin-4-ylcarbonylamino)propanamide

[0998]

[0999] TLC: Rf 0.29 (ethyl acetate:hexane=2:3);

[1000] NMR (CD₃OD): δ 7.27-7.17 (2H, m), 6.90-6.80 (2H, m), 4.67-4.43(4H, m), 4.32 (1H, d, J=15 Hz), 4.30 (1H, d, J=15 Hz), 3.76 (3H, s),3.42-3.30 (1H, m), 3.12 (1H, dd, J=12, 5 Hz), 3.00-2.70 (2H, m), 2.41(2H, d, J=6 Hz), 1.90-0.78 (11H, m), 1.45 (9H, s).

Example 6(45)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((2S)-1-t-butoxycarbonyl-pyrrolidin-2-ylcarbonylamino)propanamide

[1001]

[1002] TLC: Rf 0.38 (ethyl acetate:chloroform=1:4);

[1003] NMR (DMSO-d₆): δ 8.03-7.97 (1H, m), 7.57 (1H, d, J=8.8 Hz), 7.18(2H, d, J=8.8 Hz), 6.85 (2H, d, J=8.8 Hz), 4.45-4.40 (1H, m), 4.21 (2H,d, J=7.5 Hz), 4.15-4.12 (1H, m), 3.73 (3H, s), 3.40-3.30 (2H, m), 2.85(1H, dd, J=15.0, 8.7 Hz), 2.76 (1H, dd, J=15.0, 6.3 Hz), 2.42 (2H, d,J=3.0 Hz), 2.11-2.03 (1H, m), 1.88-1.72 (4H, m), 1.69-1.58 (3H, m),1.45-1.33 (2H, m), 1.26-1.10 (3H, m), 0.98-0.92 (2H, m).

Example 6(46)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(thiazol-4-ylcarbonyl-amino)propanamide

[1004]

[1005] TLC: Rf 0.38 (ethyl acetate:hexane=1:1);

[1006] NMR (CDCl₃): δ 8.77 (1H, d, J=1.8 Hz), 8.18 (1H, d, J=7.8 Hz),8.12 (1H, d, J=1.8 Hz), 7.25-7.18 (2H, m), 6.88-6.81 (3H, m), 4.78-4.68(1H, m), 4.51-4.33 (2H, m), 3.79 (3H, s), 3.16 (1H, dd, J=14.0, 5.6 Hz),2.92 (1H, dd, J=14.0, 7.4 Hz), 2.57-2.41 (2H, m), 1.88-0.80 (11H, m).

Example 6(47)(2R)-N-((1R)-1-(4-nitrophenyl)ethyl)-3-cyclohexylmethylthio-2-((4R)-+b3-t--butoxycarbonylthiazolidin-4-ylcarbonylamino)propanamide

[1007]

[1008] TLC: Rf 0.67 (ethyl acetate:hexane=1:1);

[1009] NMR (CDCl₃): δ 8.19-8.12 (2H, m), 7.58-7.32 (3H, m), 7.12 (1H, d,J=8.0 Hz), 5.20-5.06 (1H, m), 4.67-4.46 (4H, m), 3.40-3.15 (3H, m), 2.75(1H, dd, J=13.6, 5.8 Hz) 2.38-2.14 (2H, m), 1.80-0.64 (23H, m).

Example 6(48)(2S)-N-((1R)-1-(4-nitrophenyl)ethyl)-3-cyclohexylmethylthio-2-((4R)-+b3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino)propanamide

[1010]

[1011] TLC: Rf 0.61 (ethyl acetate:hexane=1:1);

[1012] NMR (CDCl₃): δ 8.21-8.14 (2H, m), 7.58-7.30 (3H, m), 7.05 (1H, d,J=7.4 Hz), 5.19-5.05 (1H, m), 4.65-4.47 (4H, m), 3.37-3.06 (3H, m),2.79(1H, dd, J=13.8, 6.2 Hz) 2.50 (1H, dd, J=12.4, 6.6 Hz), 2.40 (1H,dd, J=12.4, 7.0 Hz), 1.90-0.78 ((23H, m).

Example 6(49)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(2-t-butoxycarbonyl-aminothiazol-4-ylcarbonylamino)propanamide

[1013]

[1014] TLC: Rf 0.28 (ethyl acetate:hexane=2:3);

[1015] NMR (CDCl₃): δ 8.09 (1H, bs), 7.91 (1H, bd, J=8 Hz), 7.66 (1H,s), 7.25-7.15 (2H, m), 6.89-6.78 (3H, m), 4.66 (1H, td, J=8, 6),4.50-4.28 (2H, m), 3.80 (3H, s), 3.07 (1H, dd, J=14, 6 Hz), 2.91 (1H,dd, J=14, 8 Hz), 2.48 (2H, d, J=7 Hz), 1.90-0.78 (11H, m), 1.56 (9H, s).

Example 6(50)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((4S)-3-t-butoxycarbonyl-thiazolidin-4-ylcarbonylamino)propanamide

[1016]

[1017] TLC: Rf 0.34 (ethyl acetate:hexane=2:3);

[1018] NMR (CD₃OD) δ 7.27-7.17 (2H, m), 6.90-6.80 (2H, m), 4.66-4.43(4H, m), 4.40-4.23 (2H, m), 3.78 (3H, s), 3.43-3.30 (1H, m), 3.16 (1H,dd, J=12, 6 Hz), 3.08-2.75 (1H, m), 2.78 (1H, dd, J=14, 7 Hz), 2.41 (2H,d, J=7 Hz), 1.90-0.80 (11H, m), 1.43 (9H, s).

Example 6(51)(2R)-N-(4-nitrobenzyl)-3-cyclohexylmethylthio-2-((4R)-3-t-butoxycarbonyl-thiazolidin-4-ylcarbonylamino)propanamide

[1019]

[1020] TLC: Rf 0.36 (ethyl acetate:hexane=1:1);

[1021] NMR (CD₃OD) δ 8.25-8.15 (2H, m), 7.61-7.51 (2H, m), 4.70-4.41(6H, m), 3.45-3.32 (1H, m), 3.22-3.08 (1H, m), 3.04-2.72 (2H, m), 2.45(2H, d, J=7 Hz), 1.91-0.80 (11H, m), 1.45 (9H, s).

Example 6(52)(2R)-N-(4-nitrobenzyl)-3-cyclohexylmethylthio-2-((2RS)-3-t-butoxycarbonyl-thiazolidin-2-ylcarbonylamino)propanamide

[1022]

[1023] TLC: Rf 0.38 (ethyl acetate:hexane=1:1);

[1024] NMR (CD₃OD): δ 8.23-8.14 (2H, m), 7.61-7.49 (2H, m), 5.22 (1H,bs), 4.62-4.42 (3H, m), 4.00-3.87 (1H, m), 3.80-3.64 (1H, m), 3.33-2.70(4H, m), 2.45 (2H, d, J=7 Hz), 1.91-0.80 (11H, m), 1.45 and 1.40 (9H,s).

Example 6(53)(2R)-N-(4-nitrobenzyl)-3-cyclohexylmethylthio-2-((4R)-3-methylthiazolidin-4-ylcarbonylamino)propanamide

[1025]

[1026] TLC: Rf 0.32 (ethyl acetate:hexane=1:1);

[1027] NMR (CDCl₃): δ 8.23-8.16 (2H, m), 7.89 (1H, d, J=7.4 Hz),7.49-7.42 (2H, m), 7.20-7.09 (1H, m), 4.61 (1H, dd, J=15.6, 6.2 Hz),4.50 (1H, dd, J=15.6, 5.8 Hz), 4.51-4.40 (1H, m) 4.18 (1H, d, J=9.8 Hz),3.89 (1H, dd, J=9.8, 1.0 Hz), 3.79 (1H, dd, J=7.4, 2.6 Hz), 3.52 (1H,dd, J=1.0, 2.6 Hz), 3.13 (1H, dd, J=11.0, 7.4 Hz), 2.98-2.80 (2H, m),2.47 (3H, s), 2.45 (2H, d, J=7.4 Hz), 1.88-0.80 (11H, m).

Example 6(54)(2R)-N-(4-dimethylaminobenzyl)-3-cyclohexylmethylthio-2-((4R)-3-t-butoxy-carbonylthiazolidin-4-ylcarbonylamino)propanamide

[1028]

[1029] TLC: Rf 0.35 (ethyl acetate:hexane=2:3);

[1030] NMR (CD₃OD): δ 7.20-7.10 (2H, m), 6.77-6.67 (2H, m), 4.67-4.43(4H, m), 4.29 (1H, d, J=6 Hz), 4.28 (1H, d, J=6 Hz), 3.41-3.30 (1H, m),3.12 (1H, dd, J=12, 5 Hz), 3.00-2.65 (8H, m), 2.41 (2H, d, J=7 Hz),1.88-0.80 (11H, m), 1.45 (9H, s).

Example 6(55)(2R)-N-(4-dimethylaminobenzyl)-3-cyclohexylmethylthio-2-((2RS)-3-t-butoxy-carbonylthiazolidin-2-ylcarbonylamino)propanamide

[1031]

[1032] TLC: Rf 0.29 (ethyl acetate:hexane=2:3);

[1033] NMR (CD₃OD): δ 7.20-7.10 (2H, m), 6.77-6.67 (2H, m), 5.23 (1H,bs), 4.55-4.43 (1H, m), 4.40-4.16 (2H, m), 4.00-3.84 (1H, m), 3.79-3.63(1H, m), 3.30-2.66 (10H, m), 2.42 (2H, d, J=7 Hz), 1.90-0.80 (11H, m),1.45 and 1.42 (9H, s).

Example 6(56)(2R)-N-(4-nitrobenzyl)-3-cyclohexylmethylthio-2-(1-t-butoxycarbonylimidazol-4-ylcarbonylamino)propanamide

[1034]

[1035] TLC: Rf 0.48 (methylene chloride:ethyl acetate=4:1);

[1036] NMR (CDCl₃): δ 8.17 (2H, d, J=8.8 Hz), 8.03 (1H, d, J=1.4 Hz),7.98 (1H, d, J=1.4 Hz), 7.85 (1H, d, J=7.4 Hz), 7.45 (2H, d, J=8.8 Hz),7.10 (1H, t, J=6.2 Hz), 4.78-4.68 (1H, m), 4.57 (2H, d, J=6.2 Hz), 3.12(1H, dd, J=5.8, 13.6 Hz), 2.96 (1H, dd, J=7.0, 13.6 Hz), 2.50 (2H, d,J=6.6 Hz), 1.88-1.36 (15H, m), 1.30-0.90 (5H, m).

Example 6(57)(2R)-N-(4-nitrobenzyl)-3-cyclohexylmethylthio-2-((4R)-2,2-dimethylthiazolidin-4-ylcarbonylamino)propanamide

[1037]

[1038] TLC: Rf 0.47 (ethyl acetate:hexane=2:1);

[1039] NMR (CDCl₃): δ 8.24-8.17 (2H, m), 7.81 (1H, bd, J=8 Hz),7.50-7.42 (2H, m), 7.09 (1H, bt, J=6 Hz), 4.68-4.45 (3H, m), 4.16 (1H,t, J=7 Hz), 3.45 (1H, dd, J=11, 8 Hz), 3.37 (1H, dd, J=11, 7 Hz), 2.97(1H, dd, J=14, 5 Hz), 2.82 (1H, dd, J=14, 8 Hz), 2.62-2.35 (1H, b), 2.49(2H, d, J=7 Hz), 1.88-0.78 (11H, m), 1.65 (3H, s), 1.57 (3H, s).

Example 6(58)(2R)-N-(4-nitrobenzyl)-3-cyclohexylmethylthio-2-(thiophen-2-ylcarbonyl-amino)propanamide

[1040]

[1041] TLC: Rf 0.20 (hexane:ethyl acetate=2:1)

[1042] NMR (CDCl₃): δ 8.18 (2H, d, J=8.8 Hz), 7.58-7.52 (2H, m), 7.47(2H, d, J=8.8 Hz), 7.31-7.25 (1H, br), 7.11 (1H, dd, J=3.6, 5.2 Hz),7.04, (1H, d, J=6.6 Hz), 4.77-4.49 (3H, m), 3.13 (1H, dd, J=5.2, 14.0Hz), 2.87 (1H, dd, J=8.2, 14.0 Hz), 2.54 (2H, d, J=7.0 Hz), 1.88-1.37(6H, m), 1.33-0.82 (5H, m).

Example 6(59)(2R)-N-(4-nitrobenzyl)-3-cyclohexylmethylthio-2-(5-methyloxazol-2-ylcarbonyl-amino)propanamide

[1043]

[1044] TLC: Rf 0.48 (methylene chloride:ethyl acetate=4:1);

[1045] NMR (CDCl₃): δ 8.18 (2H, d, J=8.8 Hz), 7.81 (1H, d, J=7.4 Hz),7.46 (2H, d, J=8.8 Hz), 7.06 (1H, t, J=5.4 Hz), 6.88 (1H, d, J=1.2 Hz),4.75-4.49 (3H, m), 3.09 (1H, dd, J=5.8, 13.8 Hz), 2.90 (1H, dd, J=7.6,13.8 Hz), 2.59-2.46 (2H, m), 2.41 (3H, d, J=1.2 Hz), 1.88-1.37 (6H, m),1.34-0.81 (5H, m).

Example 6(60)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(3-t-butoxycarbonyl-thiazolidin-2-ylcarbonylamino)propanamide

[1046]

[1047] (The absolute configuration of * carbon is not determined, butthe above compound is a single optical isomer.)

[1048] [α]_(D)=−40.4 (c 0.1, CHCl₃);

[1049] TLC: Rf 0.19 (hexane:ethyl acetate=2:1);

[1050] NMR (CDCl₃): δ 7.21 (2H, d, J=8.4 Hz), 7.13-6.85 (2H, br), 6.84(2H, d, J=8.4 Hz), 5.24 (1H, s), 4.57-4.46 (1H, m), 4.37 (2H, d, J=5.6Hz), 3.90-3.80 (2H, m), 3.79 (3H, s), 3.22-3.03 (2H, m), 2.95 (1H, dt,J=5.2, 11.0 Hz), 2.81 (1H, dd, J=7.0, 14.0 Hz), 2.50-2.32 (2H, m),1.85-1.56 (6H, m), 1.41 (9H, s), 1.30-0.77 (5H, m).

Example 6(61)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(3-t-butoxycarbonyl-thiazolidin-2-ylcarbonylamino)propanamide

[1051]

[1052] (The absolute configuration of * carbon is not determined, butthe above compound is a single optical isomer.)

[1053] [α]_(D)=+22.0 (c 0.11, CHCl₃);

[1054] TLC: Rf 0.19 (hexane:ethyl acetate=2:1);

[1055] NMR (CDCl₃): δ 7.43-7.25 (1H, br), 7.21 (2H, d, J=8.8 Hz),6.90-6.78 (3H, m), 5.16 (1H, s), 4.61-4.20 (3H, m), 3.94-3.81 (2H, br),3.79 (3H, s), 3.40-3.02 (2H, br), 2.96 (1H, dt, J=5.0, 11.0 Hz), 2.76(1H, dd, J=7.0, 13.8 Hz), 2.50-2.31 (2H, m), 1.83-1.57 (6H, m), 1.42(9H, s), 1.29-0.77 (5H, m).

Example 6(62)(2R)-N-(4-dimethylaminobenzyl)-3-cyclohexylmethylthio-2-cyclohexyl-carbonylaminopropanamide

[1056]

[1057] TLC: Rf 0.58 (ethyl acetate:hexane=1:1);

[1058] NMR (CDCl₃): δ 7.17-7.13 (2H, m), 6.79-6.69 (3H, m), 6.51 (1H, d,J=6.6 Hz), 4.50-4.44 (1H, m), 4.34 (2H, d, J=5.4 Hz), 2.96-2.90 (7H, m),2.74 (1H, dd, J=13.5, 8.1 Hz), 2.49 (1H, dd, J=12.9, 6.9 Hz), 2.44 (1H,dd, J=12.9, 6.6 Hz), 2.18-2.08 (1H, m), 1.98-0.83 (21H, m).

Example 6(63)(2S)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(3-t-butoxycarbonyl-thiazolidin-2-ylcarbonylamino)propanamide

[1059]

[1060] (The absolute configuration of * carbon is not determined, butthe above compound is a single optical isomer.)

[1061] [α]_(D)=+31.11 (c 1.08, CHCl₃);

[1062] TLC: Rf 0.19 (ethyl acetate:hexane=1:2);

[1063] NMR (CDCl₃): δ 7.21 (2H, d, J=8.7 Hz), 7.10-6.73 (4H, m), 5.24(1H, s), 4.57-4.45 (1H, m), 4.38 (2H, d, J=5.4 Hz), 3.88-3.73 (5H, m),3.20-3.11 (2H, m), 2.99-2.92 (1H, m), 2.79 (1H, dd, J=13.8, 7.2 Hz),2.48-2.35 (2H, m), 1.83-1.58 (5H, m), 1.51-1.37 (10H, m), 1.28-1.05 (3H,m), 0.98-0.83 (2H, m).

Example 6(64)(2S)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((4S)-3-t-butoxycarbonyl-thiazolidin-4-ylcarbonylamino)propanamide

[1064]

[1065] TLC: Rf 0.57 (ethyl acetate:hexane=1:1)

[1066] NMR (CD₃OD): δ 7.25-7.18 (2H, m), 6.88-6.81 (2H, m), 4.65-4.45(4H, m), 4.35 (1H, d, J=14:6 Hz), 4.26 (1H, d, J=14.6 Hz), 3.75 (3H, s),3.35 (1H, dd, J=12.2, 7.4 Hz), 3.11 (1H, dd, J=12.2, 4.8 Hz), 2.98-2.72(2H, m), 2.41 (2H, d, J=6.6 Hz), 1.88-0.80 (20H, m).

Example 6(65)(2S)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-t-butoxycarbonyl-thiazolidin-4-ylcarbonylamino)propanamide

[1067]

[1068] TLC: Rf 0.61 (ethyl acetate:hexane=1:1);

[1069] NMR (CD₃OD): δ 7.25-7.17 (2H, m), 6.88-6.81 (2H, m), 4.64-4.44(4H, m), 4.32 (2H, br. s), 3.75 (3H, s), 3.35 (1H, dd, J=12.2, 7.4 Hz),3.13 (1H, dd, J=12.2, 5.4 Hz), 2.97 (1H, br. s), 2.76 (1H, dd, J=13.6,8.4 Hz), 2.40 (2H, d, J=7.0 HZ), 1.88-0.80 (20H, m).

Example 6(66)(2R)-N-methyl-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino)propanamide

[1070]

[1071] TLC: Rf 0.28 (ethyl acetate:hexane=1:2);

[1072] NMR (CDCl₃): δ 7.24-7.02 (3H, m), 6.90-6.83 (2H, m), 5.16-5.06(1H, m), 4.90-4.38 (5H, m), 3.80-3.79 (3H, m), 3.39-3.16 (2H, m),3.03-2.69 (5H, m), 2.44-2.23 (2H, m), 1.85-0.76 (20H, m).

Example 6(67)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-N′-methyl-N′-(3-t-butoxycarbonylthiazolidin-4-ylcarbonyl)amino)propanamide

[1073]

[1074] TLC: Rf 0.37 (ethyl acetate:hexane=1:2)

[1075] NMR (CD₃OD): δ 7.23-7.17 (2H, m), 6.86-6.82 (2H, m), 5.18-5.00(2H, m), 4.70-4.66 (1H, m), 4.49-4.18 (3H, m), 3.76 and 3.75 (3H, s),3.54-2.68 (7H, m), 2.47-2.43 (2H, m), 1.90-1.60 (5H, m), 1.50-1.05 (4H,m), 1.44 and 1.33 (9H, m), 1.05-0.87 (2H, m).

Example 6(68)(2R)-N-(4-penoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-t-butoxycarbonyl-thiazolidin-4-ylcarbonylamino)propanamide

[1076]

[1077] TLC: Rf 0.58 (ethyl acetate:hexane=1:11);

[1078] NMR (CDCl₃): δ 7.36-7.23 (5H, m), 7.15-7.07 (2H, m), 7.01-6.91(4H, m), 4.65-4.32 (6H, m), 3.33-3.13 (3H, m), 2.79 (1H, dd, J=14.1, 6.3Hz), 2.45-2.30 (2H, m), 1.83-0.78 (20H, m).

Example 6(69)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((2RS,4R)-3-t-butoxy-carbonyl-2-(2-methylpropyl)thiazolidin-4-ylcarbonylamino)propanamide

[1079]

[1080] TLC: Rf 0.32 (ethyl acetate:hexane=1:2);

[1081] NMR (CDCl₃): δ 7.40-7.19 (3H, m), 7.14 (1H, d, J=8 Hz), 6.86-6.80(2H, m), 5.20-5.07 (1H, m), 4.64 (1H, t, J=7 Hz), 4.63-4.52 (1H, m),4.43 (1H, dd, J=15, 6 Hz), 4.32 (1H, dd, J=15, 6 Hz), 3.78 (3H, s),3.36-3.15 (3H, m), 2.78 (1H, dd, J=14, 6 Hz), 2.46-2.24 (2H, m),1.91-1.53 (8H, m), 1.50-1.30 (10H, m), 1.30-1.03 (3H, m), 1.00-0.78 (8H,m).

Example 6(70)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(pyridin-3-ylcarbonyl-amino)propanamide

[1082]

[1083] TLC: Rf 0.19 (ethyl acetate:hexane=3:1);

[1084] NMR (CDCl₃): δ 9.04 (1H, dd, J=3, 1 Hz), 8.75 (1H, dd, J=5, 2Hz), 8.10 (1H, ddd, J=8, 3, 2 Hz), 7.39 (1H, ddd, J=8, 5, 1 Hz),7.43-7.36 (1H, m), 7.26-7.19 (2H, m), 6.97-6.90 (1H, m), 6.90-6.83 (2H,m), 4.72-4.63 (1H, m), 4.43 (1H, dd, J=15, 6 Hz), 4.42 (1H, dd, J=15, 6Hz), 3.79 (3H, s), 3.09 (1H, dd, J=14, 5 Hz), 2.84 (1H, dd, J=14, 8 Hz),2.54 (1H, dd, J=12, 7 Hz), 2.52 (2H, dd, J=12, 7 Hz), 1.86-1.59 (5H, m),1.56-1.39 (1H, m), 1.30-1.03 (3H, m), 1.00-0.85 (2H, m).

Example 6(71)(2R)-N-(4-benzyloxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-t-butoxy-carbonylthiazolidin-4-ylcarbonylamino)propanamide

[1085]

[1086] TLC: Rf 0.63 (ethyl acetate:hexane=1:1);

[1087] NMR (CDCl₃): δ 7.44-7.18 (8H, m), 7.13 (1H, d, J=7.8 Hz),6.93-6.88 (2H, m), 5.04 (2H, s), 4.65-4.21 (6H, m), 3.32-3.12 (3H, m),2.78 (1H, dd, J=13.8, 6.3 Hz), 2.44-2.30 (2H, m), 1.80-0.78 (20H, m).

Example 6(72)(2R)-N-(3-benzyloxy-4-methoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino)propanamide

[1088]

[1089] TLC: Rf 0.46 (hexane:ethyl acetate=1:1);

[1090] NMR (CD₃OD): δ 7.47-7.25 (5H, m), 7.00 (1H, d, J=1.4 Hz),6.92-6.83 (2H, m), 5.09 (2H, s), 4.63-4.42 (4H, m), 4.35 (1H, d, J=14.8Hz), 4.24 (1H, d, J=14.8 Hz), 3.81 (3H, s), 3.41-3.30 (1H, m), 3.12 (1H,dd, J=5.0, 12.2 Hz), 3.00-2.71 (2H, br), 2.40 (2H, d, J=7.0 Hz),1.89-1.59 (5H, m), 1.54-1.31 (10H, m), 1.29-1.08 (3H, m), 1.04-0.76 (2H,m).

Example 6(73)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(pyridin-4-ylcarbonyl-amino)propanamide

[1091]

[1092] TLC: Rf 0.23 (ethyl acetate:methylene chloride=1:1);

[1093] NMR (CDCl₃): δ 8.79-8.72 (2H, m), 7.66-7.61 (2H, m), 7.47 (1H, d,J=6 Hz), 7.26-7.19 (2H, m), 6.96-6.84 (3H, m), 4.69-4.61 (1H, m), 4.43(1H, dd, J=15, 6 Hz), 4.42 (1H, dd, J=15, 6 Hz), 3.80 (3H, s), 3.08 (1H,dd, J=14, 5 Hz), 2.82 (1H, dd, J=14, 9 Hz), 2.54 (1H, dd, J=14, 7 Hz),2.53 (2H, dd, J=14, 7 Hz), 1.86-1.75 (2H, m), 1.75-1.59 (3H, m),1.55-1.39 (1H, m), 1.30-1.03 (3H, m), 1.03-0.85 (2H, m).

Example 6(74)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((2RS,4R)-3-t-butoxycarbonyl-2-phenylthiazolidin-4-ylcarbonylamino)propanamide

[1094]

[1095] TLC: Rf 0.26 (ethyl acetate:hexane=2:3);

[1096] NMR (CDCl₃): δ 7.53-7.20 (m, 9H), 6.85-6.79 (m, 2H), 5.99 (bs,1H), 4.80 (dd, J=8, 5 Hz, 1H), 4.72-4.60 (b, 1H), 4.44 (dd, J=15, 6 Hz,1H), 4.31 (dd, J=15, 6 Hz, 1H), 3.77 (s, 3H), 3.47 (dd, J=12, 5 Hz, 1H),3.36 (dd, J=12, 8 Hz, 1H), 3.25-3.10 (b, 1H), 2.85-2.73 (m, 1H), 2.38(dd, J=12, 6 Hz, 1H), 2.29 (dd, J=12, 8 Hz, 1H), 1.78-1.56 (m, 5H),1.47-1.00 (m, 13H), 0.94-0.74 (m, 2H).

Example 6(75)(4R)-N-((1R)-2-cyclohexylmethylthio-1-(4-phenylpiperazin-1-ylcarbonyl)ethyl)-3-t-butoxycarbonylthiazolidin-4-ylcarboxamide

[1097]

[1098] TLC: Rf 0.57 (ethyl acetate:hexane=1:1);

[1099] NMR (CDCl₃): δ 7.32-7.26 (m, 2H), 7.20-7.05 (br. s, 1H),6.95-6.89 (m, 2H), 5.14-5.07 (m, 1H), 4.80-4.58 (m, 2H), 4.40 (d, J=9.3Hz, 1H), 3.88-3.66 (m, 4H), 3.38 (dd, J=11.7, 2.7 Hz 1H), 3.25-3.16 (m,5H), 2.91 (dd, J=13.8, 7.2 Hz, 1H), 2.77 (dd, J=13.8, 5.7 Hz, 1H), 2.44(d, J=6.6 Hz, 2H), 1.86-1.59 (m, 5H), 1.54-1.34 (m, 10H), 1.30-1.04 (m,3H), 0.99-0.84 (m, 2H).

Example 6(76)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((3RS)-4-t-butoxy-carbonylthiomorpholin-3ylcarbonylamino)propanamide

[1100]

[1101] TLC: Rf 0.34 (ethyl acetate:hexane=2:3),

[1102] NMR (CDCl₃): δ 7.26-7.18 (m, 2H), 7.06-6.82 (m, 4H), 5.00 (bs,1H), 4.63-4.52 (m, 1H), 4.50-4.10 (m, 3H), 3.79 (s, 3H), 3.30-3.05 (m,3H), 2.89-2.57 (m, 3H), 2.53-2.28 (m, 3H), 1.85-1.56 (m, 5H), 1.55-1.35(m, 1 OH), 1.30-1.03 (m, 3H), 1.00-0.81 (m, 2H).

Example 6(77)(2R)-N-(4-phenoxybenzyl)-3-cyclohexylmethylthio-2-((3RS)-4-t-butoxy-carbonylthiomorpholin-3-ylcarbonylamino)propanamide

[1103]

[1104] TLC: Rf 0.27 (ethyl acetate:hexane=1:2);

[1105] NMR (CDCl₃): “ 7.37-7.29 (m, 2H), 7.29-7.22 (m, 2H), 7.14-7.07(m, 1H), 7.05-6.90 (m, 6H), 5.06-4.93 (m, 11H), 4.65-4.10 (m, 4H),3.35-3.00 (m, 3H), 2.91-2.57 (m, 3H), 2.55-2.30 (m, 3H), 1.84-1.56 (m,5H), 1.56-1.35 (m, 10H), 1.30-1.03 (m, 3H), 1.00-0.83 (m, 2H).

Example 6(78)(2R)-N-(2-phenoxypyride-5-yl)-3-cyclohexylmethylthio-2-((4R)-3-t-butoxy-carbonylthiazolidin-4-ylcarbonylamino)propanamide

[1106]

[1107] TLC: Rf 0.57 (ethyl acetate:hexane=1:1);

[1108] NMR (CDCl₃): δ 8.93 (br. s, 1H), 8.49 (br. s, 1H), 8.20 (d, J=7.5Hz, 1H), 7.42-7.35 (m, 2H), 7.24-7.08 (m, 4H), 6.86 (d, J=9.0 Hz, 1H),4.80-4.70 (m, 1H), 4.66 (dd, J=7.2, 3.9 Hz, 1H), 4.60 (d, J=9.9 Hz, 1H),4.55 (d, J=9.9 Hz, 1H), 3.41-3.27 (m, 3H), 2.84 (dd, J=13.8, 5.7 Hz,1H), 2.48-2.33 (m, 2H), 1.82-1.58 (m, 5H), 1.54-1.35 (m, 10H), 1.28-1.02(m, 3H), 0.96-0.78 (m, 2H).

Example 6(79)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((2RS)-4-t-butoxy-carbonylthiomorpholin-2-ylcarbonylamino)propanamide

[1109]

[1110] TLC: Rf 0.27 (ethyl acetate:hexane=2:3);

[1111] NMR (CDCl₃): δ 7.65-7.30 (b, 1H), 7.24-7.18 (m, 2H), 6.90-6.83(m, 2H), 6.77-6.67 (b, 1H), 4.51-4.04 (m, 4H), 3.92-3.46 (m, 3H), 3.80(s, 3H), 3.40-3.29 (m, 1H), 3.03-2.92 (m, 1H), 2.90-2.67 (m, 2H),2.60-2.49 (m, 1H), 2.49-2.42 (m, 2H), 1.94-1.55 (m, 5H), 1.53-1.33 (m,10H), 1.30-1.04 (m, 3H), 1.00-0.83 (m, 2H).

Example 6(80)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((4RS)-3-t-butoxycarbonyl-1,3-perhydrothiazin-4-ylcarbonylamino)propanamide

[1112]

[1113] TLC: Rf 0.38 (ethyl acetate:hexane=2:3);

[1114] NMR (CDCl₃): δ 7.24-7.17 (m, 2H), 7.04-6.93 and 6.79-6.68 (m,2H), 6.90-6.82 (m, 2H), 4.86-4.20 (m, 6H), 3.79 (s, 3H), 3.04-2.70 (m,3H), 2.66-2.37 (m, 4H), 2.07-1.85 (m, 1H), 1.85-1.55 (m, 5H), 1.53-1.33(m, 10H), 1.30-1.04 (m, 3H), 1.00-0.83 (m, 2H).

Example 6(81)(2R)-N-(2-phenoxypyridin-5-ylmethyl)-3-cyclohexylmethylthio-2-((4R)-3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino)propanamide

[1115]

[1116] TLC: Rf 0.56 (ethyl acetate:hexane=2:1);

[1117] NMR (CDCl₃): δ 8.11 (d, J=2.4 Hz, 1H), 7.68 (dd, J=8.4, 2.4 Hz,1H), 7.50-7.35 (m, 3H), 7.22-7.16 (m, 1H), 7.14-7.08 (m, 3H), 6.84 (d,J=8.4 Hz, 1H), 4.68-4.31 (m, 6H), 3.35-3.20 (m, 3H), 2.78 (dd, J=13.8,6.0,1H), 2.44-2.28 (m, 2H), 1.82-1.60 (m, 5H), 1.51-1.36 (m, 10H),1.32-1.08 (m, 3H), 0.98-0.80 (m, 2H).

Example 6(82)(2R)-N-(4-(morpholin-4-yl)benzyl)-3-cyclohexylmethylthio-2-((4R)-3-t-butoxy-carbonylthiazolidin-4-ylcarbonylamino)propanamide

[1118]

[1119] TLC: Rf 0.34 (ethyl acetate:hexane=1:1);

[1120] NMR (CDCl₃): δ 7.20 (d, J=8.7 Hz, 1H), 7.17-7.12 (m, 2H), 6.84(d, J=8.7 Hz, 2H), 4.64 (dd, J=6.6, 4.2 Hz, 1H), 4.58 (br. s, 2H), 4.44(d, J=9.3 Hz, 1H), 4.41-4.28 (m, 2H), 3.87-3.84 (m, 4H), 3.31 (dd,J=12.3, 3.9,1H), 3.26 (dd, J=12.3,6.6 Hz, 1H), 3.20 (br. s, 1H),3.19-3.11 (m, 4H), 2.78 (dd, J=13.5, 6.3 Hz, 1H), 2.44-2.28 (m, 2H),1.82-1.60 (m, 5H), 1.5-1.34 (m, 10H), 1.31-1.04 (m, 3H), 0.96-0.80 (m,2H).

Example 6(83)(2R)-N-(4-Phenoxybenzyl)-3cyclohexylmethylthio-2-((4RS)-3-t-butoxycarbonyl-1,3-perhydrothiazin-4-ylcarbonylamino)propanamide

[1121]

[1122] TLC: Rf 0.33 ethyl acetate:hexane=1:2);

[1123] NMR (CD₃OD) δ 7.37-7.25 (m, 4H), 7.13-7.06 (m, 1H), 6.99-6.89 (m,4H), 4.94-4.30 (m, 6H), 3.08-2.87 (m, 2H), 2.87-2.76 (m, 1H), 2.68-2.50(m, 1H), 2.50-2.30 (m, 3H), 2.08-1.76 (m, 3H), 1.76-1.60 (m, 3H),1.60-1.35 (m, 1 OH), 1.35-1.07 (m, 3H), 1.03-0.85 (m, 2H).

Example 6(84)(2R)-N-(1-phenylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-3-t-butoxy-carbonylthiazolidin-4-ylcarbonylamino)propanamide

[1124]

[1125] TLC: Rf 0.46 (hexane:ethyl acetate=1:1);

[1126] NMR (CD₃OD): δ 7.24-7.18 (m, 2H), 6.97 (dd, J=8.7, 0.9 Hz, 2H),6.81 (t, J=7.5 Hz, 1H), 4.65-4.56 (m, 2H), 4.50-4.45 (m, 2H), 3.86-3.76(m, 1H), 3.68-3.57 (br, 2H), 3.43-3.32 (br, 1H), 3.16 (dd, J=12.0, 4.8Hz, 1H), 2.94-2.77 (m, 4H), 2.46 (d, J=6.6 Hz, 2H), 2.00-1.79 (br, 4H),1.78-1.59 (m, 5H), 1.52-1.38 (m, 10H), 1.33-1.09 (m, 3H), 1.01-0.89 (m,2H).

Example 6(85)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-2-oxothiazolidin-4-ylcarbonylamino)propanamide

[1127]

[1128] TLC: Rf 0.30 (ethyl acetate:hexane=2:1);

[1129] NMR (CDCl₃): δ 7.72-7.58 (1H, m), 7.30-7.11 (3H, m), 7.11-6.96(1H, m), 6.89-6.79 (2H, m), 4.59 (1H, q, J=7 Hz), 4.45-4.18 (3H, m),3.78 (3H, s), 3.69 (1H, dd, J=11, 8 Hz), 3.57 (1H, dd, J=11, 5 Hz), 2.86(2H, d, J=7 Hz), 2.43 (2H, d, J=7 Hz), 1.86-0.75 (11 Hz m).

Example 6(86)(2R)-N-(1-methylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-3-t-butoxy-carbonylthiazolidin-4-ylcarbonylamino)propanamide

[1130]

[1131] TLC: Rf 0.44 (chloroform:methanol=9:1);

[1132] NMR (CD₃OD): δ 4.65-4.56 (m, 2H), 4.49-4.43 (m, 2H), 3.72-3.62(m, 1H), 3.42-3.33 (m, 1H), 3.14 (dd, J=12.0, 4.8 Hz, 1H), 2.93-2.70(br, 4H), 2.45 (d, J=6.9 Hz, 2H), 2.30 (s, 3H), 2.26-2.14 (br, 2H),1.93-1.79 (br, 4H), 1.76-1.37 (m, 15H), 1.33-1.09 (m, 3H), 1.02-0.88 (m,2H).

Example 7(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylsulfonyl-2-t-butoxycarbonyl-aminopropanamide

[1133]

[1134] A solution of the compound prepared in Example 2(80) (147 mg) inmethylene chloride (5 ml) was cooled to −78° C. and m-chloroperbenzoicacid (117 mg) was added thereto. The mixture was stirred for 70 minutes.The reaction mixture was warmed to room temperature with stirring for3.5 hours. To the reaction mixture, m-chloroperbenzoic acid (10 mg) wasadded. The reaction mixture was stirred for 1 hour. The reaction mixturewas diluted with chloroform, washed with saturated aqueous sodiumhydrogencarbonate, saturated aqueous sodium thiosulfate and saturatedaqueous sodium chloride, successively, dried over anhydrous magnesiumsulfate. The organic layer was concentrated and the residue was purifiedby recrystallization (ethyl acetate) to give the compound of the presentinvention (101 mg) having the following physical data.

[1135] TLC: Rf 0.25 (ethyl acetate:hexane=1:2);

[1136] NMR (CDCl₃): δ 7.24-7.17 (2H, m), 7.00 (1H, t, J=5.6 Hz),6.89-6.82 (2H, m), 5.84 (1H, d, J=8.2 Hz), 4.66 (1H, dt, J=8.0, 5.0 Hz),4.47 (1H, dd, J=15.0, 5.8 Hz), 4.31 (1H, dd, J=15.0, 5.6 Hz), 3.79 (3H,s), 3.70 (1H, dd, J=14.6, 5.0 Hz), 3.39 (1H, dd, J=14.6, 5.2 Hz),3.09-2.91 (2H, m), 2.16-0.96 (20H, m).

Example 7(1)˜7(4)

[1137] By the same desired procedure as Example 7, using the compoundsprepared in Example 2(80), Example 2(90), Example 2(95) and Example6(31), the following compounds of the present invention were obtained.

Example 7(1)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylsulfinyl-2-t-butoxycarbonyl-aminopropanamide

[1138]

[1139] TLC: Rf 0.51 (methanol:chloroform=1:19);

[1140] NMR (CDCl₃): δ 7.65 (0.33H, br.s), 7.37-7.17 (2.67H, m),6.89-6.81 (2H, m), 6.39-6.27 (0.67H, m), 5.87 (0.33H, d, J=5.8 Hz),4.80-4.60 (1H, m), 4.51-4.28 (2H, m), 3.79 (3H, s), 3.34-3.21 (1H, m),3.01-2.86 (1H, m), 2.78-2.66 (1H, m); 2.55-2.45 (1H, m), 2.02-0.92 (20H,m).

Example 7(2)(2R)-N-(4-methoxybenzyl)-3-cyclopentylmethylsulfonyl-2-t-butoxycarbonyl-aminopropanamide

[1141]

[1142] TLC: Rf 0.21 (ethyl acetate:hexane=1:2);

[1143] NMR (CDCl₃): δ 7.25-7.18 (2H, m), 6.99 (1H, t, J=4.8 Hz),6.90-6.82 (2H, m), 5.84 (1H, d, J=8.0 Hz), 4.71-4.62 (1H, m), 4.47 (1H,dd, J=14.6, 6.2 Hz), 4.32 (1H, dd, J=14.6, 5.4 Hz), 3.81-3.68 (4H, m),3.40 (1H, dd, J=15.0, 5.2 Hz), 3.20 (1H, dd, J=14.2, 6.8 Hz), 3.11 (1H,dd, J=14.2, 6.8 Hz), 2.46-2.26 (1H, m), 2.05-1.91 (2H, m), 1.75-1.19(15H, m).

Example 7(3)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylsulfonyl-2-cyclohexylcarbonyl-aminopropanamide

[1144]

[1145] TLC: Rf 0.18 (chloroform: ethyl acetate=100:15);

[1146] NMR (CDCl₃): δ 7.26-7.15 (3H, m), 6.93-6.82 (3H, m), 4.84 (1H,td, J=6.6, 4.4 Hz), 4.44 (1H, dd, J=14.6, 5.8 Hz), 4.31 (1H, dd, J=14.6,5.4 Hz), 3.79 (3H, s), 3.63 (1H, dd, J=15.0, 4.4 Hz), 3.30 (1H, dd,J=15.0, 6.2 Hz), 3.17 (1H, dd, J=14.2, 6.6 Hz), 3.07 (1H, dd, J=14.2,6.2 Hz), 2.24-1.00 (22H, m).

Example 7(4)(2S)-N-(4-methoxybenzyl)-3-cyclopentylmethylsulfonyl-2-t-butoxycarbonyl-aminopropanamide

[1147]

[1148] TLC: Rf 0.22 (ethyl acetate:hexane=1:2);

[1149] NMR (CDCl₃): δ 7.25-7.17 (2H, m), 6.97 (1H, t, J=5.4 Hz),6.90-6.82 (2H, m), 5.82 (1H, d, J=8.4 Hz), 4.71-4.62 (1H, m), 4.48 (1H,dd, J=14.8, 6.4 Hz), 4.32 (1H, dd, J=14.8, 5.4 Hz), 3.79-3.68 (4H, m),3.39 (1H, dd, J=14.6, 5.0 Hz), 3.21 (1H, dd, J=14.2, 7.4 Hz), 3.11 (1H,dd, J=14.2, 7.0 Hz), 2.46-2.30 (1H, m), 2.05-1.91 (2H, m), 1.75-1.17(15H, m);

Example 8˜Example 8(12)

[1150] By the same desired procedure as Example 6, using the compoundsprepared in Example 7 and Example 7(1), the following compounds of thepresent invention were obtained.

[1151] Also, (+)-3-t-butoxycarbonylthiazolidin-2-ylcarboxylic acid wasused for the preparation of the compound of Example 8(8).

Example 8(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylsulfonyl-2-(4-methoxy-cyclohexylcarbonylamino)propanamide

[1152]

[1153] (The relative configuration of cyclohexyl ring substituted bymethoxy group is not determined, but the above compound is a singlecompound. This compound is the isomer of the compound prepared inExample 8(1).) more polar

[1154] TLC: Rf 0.68 (ethyl acetate)

[1155] NMR (CDCl₃): δ 7.30-7.24 (1H, m), 7.22-7.15 (2H, m), 6.97 (1H, d,J=6.6 Hz), 6.89-6.82 (2H, m), 4.90-4.81 (1H, m), 4.42 (1H, dd, J=4.6,5.8 Hz), 4.30 (1H, dd, J=14.6, 5.6 Hz), 3.79 (3H, s), 3.60 (1H, dd,J=15.0, 4.8 Hz), 3.45-3.26 (5H, m), 3.15(1H, dd, J=140, 6.2 Hz),3.05(1H, dd, J=14.0, 6.2 Hz), 2.28-1.00 (20H, m).

Example 8(1)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylsulfonyl-2-(4-methoxy-cyclohexylcarbonylamino)propanamide

[1156]

[1157] (The relative configuration of cyclohexyl ring substituted bymethoxy group is not determined, but the above compound is a singlecompound. This compound is the isomer of the compound prepared inExample 8.) less polar

[1158] TLC: Rf 0.59 (ethyl acetate)

[1159] NMR (CDCl₃): δ 7.28-7.14 (3H, m), 6.94 (1H, d, J=7.0 Hz),6.89-6.82 (2H, m), 4.91-4.82 (1H, m), 4.42 (1H, dd, J=14.6, 5.8 Hz),4.30 (1H, dd, J-14.6, 5.4 Hz), 3.79 (3H, s), 3.60 (1H, dd, J=15.0, 4.8Hz), 3.38-3.24 (4H, m), 3.18-2.99 (3H, m), 2.21-1.00 (20H, m).

Example 8(2)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmehtylsulfonyl-2-cyclobutyl-carbonylaminopropanamide

[1160]

[1161] TLC: Rf 0.26 (ethyl acetate:hexane=1:1);

[1162] NMR (CDCl₃): δ 7.30-7.15 (3H, m), 6.89-6.78 (3H, m), 4.89-4.80(1H, m), 4.43 (1H, dd, J=14.6, 5.8 Hz), 4.31 (1H, dd, J=14.6, 5.6 Hz),3.79 (3H, s), 3.62 (1H, dd, J=15.0, 4.2 Hz), 3.31 (1H, dd, J=15.0, 6.6Hz), 3.23-2.98 (3H, m), 2.38-1.01 (17H, m).

Example 8(3)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylsulfonyl-2-(tetrahydrofuran-2-ylcarbonylamino)propanamide

[1163]

[1164] TLC: Rf 0.14 (ethyl acetate:hexane=1:1);

[1165] NMR (CDCl₃): δ 7.82-7.77 (1H, m), 7.23-7.05 (3H, m), 6.89-6.82(2H, m), 4.99-4.90 (0.5H, m), 4.85-4.75 (0.5H, m), 4.49-4.27 (3H, m),4.09-3.79 (5H, m), 3.73-3.33 (2H, m), 3.21-2.94 (2H, m), 2.38-0.98 (15H,m).

Example 8(4)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylsulfonyl-2-cycloheptylcarbonyl-aminopropanamide

[1166]

[1167] TLC: Rf 0.14 (ethyl acetate:hexane=1:2);

[1168] NMR (CDCl₃): δ 7.26-7.15 (3H, m), 6.89-6.82 (3H, m), 4.88-4.79(1H, m), 4.44 (1H, dd, J=14.8, 6.0 Hz), 4.30 (1H, dd, J=14.8, 5.6 Hz),3.79 (3H, s), 3.61 (1H, dd, J=15.0, 4.4 Hz), 3.31 (1H, dd, J=15.0, 6.2Hz), 3.17 (1H, dd, J=14.0, 6.2 Hz), 3.06 (1H, dd, J=14.0, 5.8 Hz),2.38-1.00 (24H, m).

Example 8(5)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylsulfonyl-2-(tetrahydrofuran-3-ylcarbonylamino)propanamide

[1169]

[1170] TLC: Rf 0.08 (ethyl acetate:hexane=1:1);

[1171] NMR (CD₃OD): δ 7.25-7.15 (3H, m), 7.02 (1H, d, J=7.0 Hz),6.90-6.82 (2H, m), 4.88-4.80 (1H, m), 4.43 (1H, dd, J=14.8, 6.0 Hz),4.31 (1H, dd, J=14.8, 5.6 Hz), 4.01-3.73 (7H, m), 3.64-3.54 (1H, m),3.39-3.27 (1H, m), 3.21-2.89 (3H, my, 2.20-1.00 (13H, m).

Example 8(6)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylsulfonyl-2-((2RS)-3-t-butoxy-carbonylthiazolidin-2-ylcarbonylamino)propanamide

[1172]

[1173] TLC: Rf 0.32 (ethyl acetate:hexane=1:1);

[1174] NMR (CD₃OD): δ 7.23 (2H, d, J=9 Hz), 6.85 (2H, d, J=9 Hz), 5.20(s) and 5.16 (bs) (1H), 4.97-4.84 (1H, m), 4.42-4.23 (2H, m), 4.02-3.85(1H, m), 3.84-3.60 (2H, m), 3.77 (3H, s), 3.53-3.10 (2H, m), 3.08-2.90(3H, m), 2.20-1.58 (6H, m), 1.44 and 1.40 (9H, s), 1.35-1.00 (5H, m).

Example 8(7)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylsulfonyl-2-((4R)-3-t-butoxy-carbonylthiazolidin-4-ylcarbonylamino)propanamide

[1175]

[1176] TLC: Rf 0.61 (methylene chloride:ethyl acetate=2:1);

[1177] NMR (CDCl₃): δ 7.96 (1H, brs), 7.67 (1H, brs), 7.25-7.22 (2H, m),6.84-6.82 (2H, m), 5.02-4.91 (1H, m), 4.62-4.42 (4H, m), 4.30 (1H, dd,J=14.4, 5.0 Hz), 4.06-3.92 (1H, m), 3.78 (3H, s), 3.34-3.15 (3H, m),2.93-2.72 (2H, m), 2.10-1.59 (6H, m), 1.40 (9H, s), 1.50-0.85 (5H, m).

Example 8(8)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylsulfonyl-2-(3-t-butoxycarbonyl-thiazolidin-2-ylcarbonylamino)propanamide

[1178]

[1179] (The absolute configuration of * carbon is not determined, butthe above compound is a single optical isomer.)

[1180] [α]_(D)=+1.23 (c 1.31, CHCl₃)

[1181] TLC: Rf 0.63 (methylene chloride:ethyl acetate=2:1);

[1182] NMR (CD₃OD): δ 7.23-7.18 (2H, m), 6.86-6.81 (2H, m), 5.16 (1H.br), 4.96-4.84 (1H, m), 4.40-4.23 (2H, m), 4.00-3.82 (1H, m), 3.80-3.50(2H, m), 3.75 (3H, s), 3.50-3.10 (2H, m), 3.09-2.95 (1H, m), 3.00 (2H,d, J=6.2 Hz), 2.17-1.80 (3H, m), 1.80-1.55 (3H, m), 1.39 (9H, s),1.42-1.00 (5H, m).

Example 8(9)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylsulfinyl-2-((4R)-3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino)propanamide

[1183]

[1184] TLC: Rf 0.65 (chloroform:methanol=14:1);

[1185] NMR (CD₃OD): δ 7.23-7.18 (2H, m), 6.87-6.83 (2H, m), 4.90-4.75(1H, m), 4.63-4.45 (3H, m), 4.34-4.32 (2H, m), 3.76 (3H, s), 3.41-3.05(4H, m), 2.84-2.59 (2H, m), 2.01-1.60 (6H, m), 1.43 and 1.42 (9H, s),1.43-1.00 (5H, m).

Example 8(10)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylsulfonyl-2-(1-t-butoxycarbonylapiperidin-4-ylcarbonylamino)propanamide

[1186]

[1187] TLC: Rf 0.25 (ethyl acetate:chloroform=2:3);

[1188] NMR (CDCl₃): δ 7.28-7.15 (3H, m), 6.97 (1H, d, J=6.6 Hz),6.90-6.82 (2H, m), 4.88-4.79 (1H, m), 4.43 (1H, dd, J=4.2, 5.8 Hz), 4.31(1H, dd, J=14.2, 5.4 Hz), 4.22-4.04 (2H, m), 3.79 (3H, s), 3.61 (1H, dd,J=15.2, 4.8 Hz), 3.30 (1H, dd, J=15.2, 6.6 Hz), 3.16 (1H, dd, J=14.4,6.6 Hz), 3.06 (1H, dd, J=14.4, 6.2 Hz), 2.79-2.66 (2H, m), 2.39-1.00(25H, m).

Example 8(11)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylsulfonyl-2-(4-t-butozycarbonylaminocyclohexylcarbonylamino)propanamide

[1189]

[1190] (The relative configuration of cyclohexyl ring substituted byt-butoxycarbonylamino group is not determined, but the above compound isa single compound. This compound is the isomer of the compound preparedin Example 8(12).)

[1191] TLC: Rf 0.17 (ethyl acetate:chloroform=3:7);

[1192] NMR (CDCl₃): δ 7.27-7.15 (3H, m), 6.97 (1H, d, J=7.0 Hz),6.90-6.82 (2H, m), 4.90-4.81 (1H, m), 4.67 (1H, d, J=7.6 Hz), 4.43 (1H,dd, J=14.6, 5.8 Hz), 4.31 (1H, dd, J=14.6, 6.0 Hz), 3.79-3.57 (5H, m),3.32 (1H, dd, J=15.0, 6.2 Hz), 3.17 (1H, dd, J=14.2, 6.6 Hz), 3.05 (1H,dd, J=14.2, 6.2 Hz), 2.34-1.00 (29H, m).

Example 8(12)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylsulfonyl-2-(4-t-butoxycarbonylaminocyclohexylcarbonylamino)propanamide

[1193]

[1194] (The relative configuration of cyclohexyl ring substituted byt-butoxycarbonylamino group is not determined, but the above compound isa single compound. This compound is the isomer of the compound preparedin Example 8(11).)

[1195] TLC: Rf 0.17 (ethyl acetate:chloroform=3:7);

[1196] NMR (CDCl₃): δ 7.28-7.14 (3H, m), 6.95 (1H, d, J=6.6 Hz),6.89-6.82 (2H, m), 4.88-4.79 (1H, m), 4.47-4.24 (3H, m), 3.79 (3H, s),3.60 (1H, dd, J=15.0, 4.8 Hz), 3.50-3.25 (2H, m), 3.15 (1H, dd, J=14.4,6.4 Hz), 3.05 (1H, dd, J=14.4, 6.2 Hz), 2.18-0.96 (29H, m).

Example 9˜Example 9(16)

[1197] By the same desired procedure as Reference Example 4, using thecompounds prepared in Example 6(36), Example 6(39), Example 6(40),Example 6(41), Example 6(44), Example 6(47), Example 6(50)˜Example6(52), Example 6(54)˜Example 6(56), Example 6(71), Example 6(72),Example 6(84) and Example 8(6), the following compounds of the presentinvention were obtained.

Example 9(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((2RS)-thoazolidin-2-ylcarbonylamino)propanamide.hydrochloride

[1198]

[1199] TLC: Rf 0.27 (methylene chloride:methanol=97:3);

[1200] NMR (CD₃OD) δ 7.22 (2H, d, J=9 Hz), 6.85 (2H, d, J=9 Hz), 5.41and 5.39 (1H, s), 4.55-4.44 (1H, m), 4.36-4.26 (2H, m), 3.85-3.70 (1H,m), 3.76 (3H, s), 3.70-3.52 (1H, m), 3.40-3.10 (2H, m), 3.00-2.84 (1H,m), 2.84-2.68 (1H, m), 2.46-2.38 (2H, m), 1.90-1.55 (5H, m), 1.55-1.08(4H, m), 1.07-0.77 (2H, m).

Example 9(1)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylsulfonyl-2-((2RS)-thoazolidin-2-ylcarbonylamino)propanamide.hydrochloride

[1201]

[1202] TLC: Rf 0.25 (methylene chloride:methanol=97:3);

[1203] NMR (CD₃OD) δ 7.22 (2H, d, J=9 Hz), 6.86 (2H, d, J=9 Hz), 5.44(s) and 5.37 (1H, s), 5.03-4.93 (1H, m), 4.42-4.22 (2H, m), 3.84-3.34(4H, m), 3.77 (3H, s), 3.34-3.12 (2H, m), 3.05 (2H, d, J=6 Hz),2.10-1.83 (3H, m), 1.83-1.58 (3H, m), 1.50-1.00 (5H, m).

Example 9(2)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(piperidin-4-ylcarbonylamino)propanamide.hydrochloride

[1204]

[1205] TLC: Rf 0.19 (chloroform:methanol=9:1);

[1206] NMR (DMSO-d₆): δ 9.06-8.90 (1H. br), 8.74-8.52 (2H, m), 8.19 (1H,d, J=8.4 Hz), 7.18 (2H, d, J=8.8 Hz), 6.86 (2H, d, J=8.8 Hz), 4.48-4.37(1H, m), 4.21 (2H, d, J=6.0 Hz), 3.73 (3H, s), 3.33-3.23 (2H, br),2.96-2.76 (3H, m), 2.59 (1H, dd, J=8.8, 13.4 Hz), 2.55-2.43 (1H, m),2.39 (2H, d, J=7.0 Hz), 1.94-1.52 (9H, m), 1.49-1.03 (4H, m), 0.99-0.77(2H, m).

Example 9(3)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(4-aminocyclohexyl-carbonylamino)propanamide.hydrochloride

[1207]

[1208] (The relative configuration of cyclohexyl ring substituted byamino group is not determined, but the above compound is a singlecompound. This compound is the isomer of the compound prepared inExample 9(4).)

[1209] TLC: Rf 0.16 (chloroform:methanol=9:1);

[1210] NMR (DMSO-d₆): δ 8.49 (1H, d, J=6.0 Hz), 8.06-7.85 (4H, m), 7.18(2H, d, J=8.8 Hz), 6.86 (2H, d, J=8.8 Hz), 4.47-4.36 (1H, m), 4.21 (2H,d, J=6.0 Hz), 3.73 (3H, s), 3.17-3.04 (1H, br), 2.82 (1H, dd, J=5.6,13.4 Hz), 2.64 (1H—, dd, J=8.6, 13.4 Hz), 2.44-2.31 (3H, m), 1.99-1.49(12H, m), 1.46-1.03 (5H, m), 0.98-0.76 (2H, m).

Example 9(4)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(4-aminocyclohexyl-carbonylamino)propanamide.hydrochloride

[1211]

[1212] (The relative configuration of cyclohexyl ring substituted byamino group is not determined, but the above compound is a singlecompound. This compound is the isomer of the compound prepared inExample 9(3).)

[1213] TLC: Rf 0.11 (chloroform:methanol=9:1);

[1214] NMR (DMSO-d₆): δ 8.53-8.47 (1H, br), 8.05-7.94 (4H, br), 7.17(2H, d, J=8.4 Hz), 6.85 (2H, d, J=8.4 Hz), 4.45-4.35 (1H, br), 4.19 (2H,br), 3.72 (3H, s), 3.16 (1H, d, J=5.2 Hz), 3.04-2.88 (1H, br), 2.78 (1H,dd, J=5.8, 13.2 Hz), 2.59 (1H, dd, J=8.2, 13.2 Hz), 2.38 (2H, d, J=6.6Hz), 2.35-2.08 (2H, br), 1.98-1.55 (8H, m), 1.49-1.02 (7H, m), 0.99-0.77(2H, m).

Example 9(5)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-thiazolidin-4-ylcarbonylamino)propanamide.hydrochloride

[1215]

[1216] TLC: Rf 0.26 (methylene chloride:methanol=97:3);

[1217] NMR (CD₃OD): δ 7.27-7.17 (2H, m), 6.93-6.80 (2H, m), 4.61-4.47(2H, m), 4.41 (2H, s), 4.33 (1H, d, J=14 Hz), 4.31 (1H, d, J=14 Hz),3.77 (3H, s), 3.55 (1H, dd, J=12, 7), 3.22 (1H, dd, J=12, 7 Hz), 2.92(1H, dd, J=14, 7 Hz), 2.80 (1H, dd, J=14, 8 Hz), 2.43 (2H, d, J=6 Hz),1.90-0.80 (11H, m).

Example 9(6)(2R)-N-((1R)-1-(4-nitrophenyl)ethyl)-3-cyclohexylmethylthio-2-((4R)-thiazolidin-4-ylcarbonylamino)propanamide.hydrochloride

[1218]

[1219] TLC: Rf 0.74 (methanol:chloroform=5:95);

[1220] NMR (CD₃OD) δ 8.92 (1H, d, J=7.2 Hz), 8.21-8.14 (2H, m),7.60-7.54 (2H, m), 5.12-4.98 (1H, m), 4.55 (2H, t, J=7.0 Hz), 4.44 (1H,d, J=10.2 Hz), 4.38 (1H, d, J=10.2 Hz) 3.51 (1H, dd, J=12.2, 7.4 Hz),3.12 (1H, dd, J=12.2, 7.0 Hz), 2.94 (1H, dd, J=13.6, 6.6 Hz), 2.80 (1H,dd, J=13.4, 8.2 Hz), 2.50 (2H, d, J=6.6 Hz), 1.93-0.85 (14H, m).

Example 9(7)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((4S)-thiazolidin-4-ylcarbonylamino)propanamide.hydrochloride

[1221]

[1222] TLC: Rf 0.44 (methylene chloride:methanol=19:1);

[1223] NMR (CD₃OD): δ 7.29-7.18 (2H, m), 6.91-6.81 (2H, m), 4.65-4.51(2H, m), 4.44 (1H, d, J=11 Hz), 4.43 (1H, d, J=11 Hz), 4.32 (2H, m),3.77 (3H, s), 3.59 (1H, dd, J=12, 8 Hz), 3.38-3.26 (1H, m), 2.97 (1H,dd, J=14, 5 Hz), 2.76 (1H, dd, J=14, 9 Hz), 2.42 (2H, d, J=7 Hz),1.89-0.80 (11H, m).

Example 9(8)(2R)-N-(4-nitrobenzyl)-3-cyclohexylmethylthio-2-((4R)-thiazolidin-4-ylcarbonylamino)propanamide.hydrochloride

[1224]

[1225] TLC: Rf 0.43 (methylene chloride:methanol=19:1);

[1226] NMR (CD₃OD): δ 8.25-8.15 (2H, m), 7.62-7.50 (2H, m), 4.63-4.49(4H, m), 4.43, (1H, d, J=10 Hz), 4.41 (1H, d, J=10 Hz), 3.56 (1H, dd,J=12, 7 Hz), 3.26 (1H, dd, J=12, 7 Hz), 2.96 (1H, dd, J=13, 7 Hz), 2.85(1H, dd, J=13, 8 Hz), 2.46 (2H, d, J=7 Hz), 1.91-0.80 (11H, m).

Example 9(9)(2R)-N-(4-nitrobenzyl)-3-cyclohexylmethylthio-2-((2RS)-thiazolidin-2-ylcarbonylamino)propanamide.hydrochloride

[1227]

[1228] TLC: Rf 0.41 (methylene chloride:methanol=19:1);

[1229] NMR (DMSO-d,): δ 9.10-8.93 (2H, m), 8.24-8.14 (2H, m), 7.62-7.52(2H, m), 5.35 and 5.27 (1H, s), 4.58-4.39 (3H, m), 3.72-3.46 (2H, m),3.28-3.03 (2H, m), 2.94-2.64 (2H, m), 2.44 (2H, d, J=7 Hz), 1.94-0.75(11H, m).

Example 9(10)(2R)-N-(4-nitrobenzyl)-3-cyclohexylmethylthio-2-(imidazol-4-ylcarbonylamino)propanamide.hydrochloride

[1230]

[1231] TLC: Rf 0.31 (chloroform:methanol=9:1);

[1232] NMR (DMSO-d₆): δ 9.10-9.01 (3H, m), 8.28 (1H, s), 8.18 (2H, d,J=8.8 Hz), 7.56 (2H, d, J=8.8 Hz), 4.73-4.61 (1H, m), 4.40 (2H, d, J=6.0Hz), 2.98 (1H, dd, J=6.0, 13.6 Hz), 2.82 (1H, dd, J=8.4, 13.6 Hz), 2.45(2H, d, J=7.0 Hz), 1.80-1.30 (6H, m), 1.28-0.78 (5H, m).

Example 9(11)(2R)-N-(4-dimethylaminobenzyl)-3-cyclohexylmethylthio-2-((4R)-thiazolidin-4-ylcarbonylamino)propanamide.2hydrochloride

[1233]

[1234] TLC: Rf 0.42 (methylene chloride:methanol=19:1);

[1235] NMR (CD₃OD): δ 7.67-7.60 (2H, m), 7.60-7.50 (2H, m), 4.66-4.37(6H, m), 3.59 (1H, dd, J=12, 8 Hz), 3.33-3.21 (1H, m), 3.28 (6H, s),2.94 (1H, dd, J=16, 7 Hz), 2.84 (1H, dd, J=16, 8 Hz), 2.48 (2H, d, J=7Hz), 1.93-0.83 (11H, m).

Example 9(12)(2R)-N-(4-dimethylaminobenzyl)-3-cyclohexylmethylthio-2-((2RS)-thiazolidin-2-ylcarbonylamino)propanamide.2hydrochloride

[1236]

[1237] TLC: Rf 0.40 (methylene chloride:methanol=19:1);

[1238] NMR (CD₃OD): δ 7.68-7.59 (2H, m), 7.59-7.51 (2H, m), 5.47 and5.42 (1H, s), 4.59-4.43 (3H, m), 3.92-3.76 (1H, m), 3.72-3.68 (1H, m),3.39-3.17 (2H, m), 3.29 (6H, m), 3.07-2.73 (2H, m), 2.47 (2H, d, J=7Hz), 1.93-0.83 (11H, m).

Example 9(13)(2R)-N-(4-phenoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-thiazolidin-4-ylcarbonylamino)propanamide.hydrochloride

[1239]

[1240] TLC: Rf 0.65 (ethyl acetate)

[1241] NMR (CD₃OD): δ 8.71 (1H, t, J=5.7 Hz), 7.36-7.28 (4H, m), 7.09(1H, t, J=7.2 Hz), 6.96-6.89 (4H, m), 4.59-4.51 (2H, m), 4.44-4.30 (4H,m), 3.55 (1H, dd, J=11.7, 7.5 Hz), 3.24 (1H, dd, J=11.7, 6.9 Hz), 2.93(1H, dd, J=13.5, 6.3 Hz), 2.81 (1H, dd, J=13.5, 7.5 Hz), 2.46 (1H, dd,J=12.6, 6.9 Hz), 2.42 (1H, dd, J=12.6, 6.6 Hz), 1.88-1.79 (2H, m),1.74-1.61 (3H, m), 1.53-1.36 (1H, m), 1.31-1.08 (3H, m), 1.00-0.88 (2H,m).

Example 9(14)(2R)-N-(4-benzyloxybenzyl)-3-cyclohexylmethylthio-2-((4R)-thiazolidin-4-ylcarbonylamino)propanamide.hydrochloride

[1242]

[1243] TLC: Rf 0.30 (ethyl acetate:hexane=1:1);

[1244] NMR (CD₃OD): δ 8.81 (1H, d, J=8.1 Hz), 8.63 (1H, t, J=7.5 Hz),7.43-7.19 (7H, m), 6.95-6.69 (2H, m), 5.05 (2H, s), 4.60-4.25 (6H, m),3.56 (1H, dd, J=12.3, 7.5 Hz), 3.21 (1H, dd, J=12.3, 7.2 Hz), 2.91 (1H,dd, J=13.8, 6.6 Hz), 2.78 (1H, dd, J=13.8, 7.5 Hz), 2.44 (1H, dd, J=2.6,6.9 Hz), 2.40 (1H, dd, J=12.6, 6.6 Hz), 1.86-0.83 (11H, m).

Example 9(15)(2R)-N-(3-benzyloxy-4-methoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-thiazolidin-4-ylcarbonylamino)propanamide.hydrochloride

[1245]

[1246] TLC: Rf 0.27 (hexane:ethyl acetate=1:1);

[1247] NMR (CD₃OD): δ 7.47-7.26 (m, 5H), 7.00 (d, J=1.8 Hz, 1H), 6.91(d, J=8.2 Hz, 1H), 6.88 (dd, J=8.2, 1.8 Hz, 1H), 5.08 (s, 2H), 4.60-4.48(m, 2H), 4.39 (s, 2H), 4.36 (d, J=14.8 Hz, 1H), 4.23 (d, J=14.8 Hz, 1H),3.82 (s, 3H), 3.56 (dd, J=12.2, 7.4 Hz, 1H), 3.22 (dd, J=12.2, 7.0 Hz,1H), 2.91 (dd, J=13.8, 6.6 Hz, 1H), 2.77 (dd, J=13.8, 7.8 Hz, 1H), 2.42(d, J=6.8 Hz, 2H), 1.85-1.56 (m, 5H), 1.54-0.80 (m, 6H).

Example 9(16)(2R)-N-(1-phenylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-thiazolidin-4-ylcarbonylamino)propanamide.2hydrochloride

[1248]

[1249] TLC: Rf 0.26 (hexane:ethyl acetate=1:1);

[1250] NMR (CD₃OD) δ 7.80-7.76 (m, 2H), 7.65-7.54 (m, 3H), 4.63 (t,J=7.2 Hz, 1H), 4.54 (t, J=7.2 Hz, 1H), 4.45 (d, J=9.9 Hz, 1H), 4.42 (d,J=9.9 Hz, 1H), 4.20-4.10 (m, 1H), 3.87-3.70 (br, 4H), 3.61 (dd, J=12.0,7.5 Hz, 1H), 3.29 (dd, J=0.12.0, 6.9 Hz, 1H), 2.95 (dd, J=13.2, 6.6 Hz,1H), 2.83 (dd, J=13.2, 7.8 Hz, 1H), 2.57-2.46 (m, 2H), 2.32-2.14 (m,4H), 1.90-1.81 (br, 2H), 1.77-1.63 (m, 3H), 1.54-1.40 (m, 1H), 1.36-1.10(m, 3H), 1.03-0.91 (m, 2H).

Reference Example 5Bis((2R)-2-(4-methoxybenzylcarbamoyl)-2-t-butoxycarbonylaminoethyl)-disulfide

[1251]

[1252] Bis((2R)-carboxy-2-t-butoxycarbonylaminoethyl)disulfide (5 g),4-methoxybenzylamine (3.7 ml) and 1-hydroxybenzotriazole (3.84 g) weredissolved in a mixture of methylene chloride (50 ml) and DMF (10 ml).The solution was cooled with ice and EDC-HCl (5.45 g) was added thereto.The mixture was stirred for 12 hours. The reaction mixture was dilutedwith chloroform, washed with 1N hydrochloric acid, saturated aqueoussodium hydrogencarbonate and saturated aqueous sodium chloride,successively, dried over anhydrous magnesium sulfate. The organic layerwas concentrated and the residue was washed with diehylether to give thetitle compound (8.15 g) having the following physical data.

[1253] TLC: Rf 0.16 (ethyl acetate:hexane=1:2);

[1254] NMR (CDCl₃): 8.03 (2H, t, J=6.3 Hz), 7.23-7.15 (4H, m), 6.87-6.80(4H, m), 5.54 (2H, d, J=9.6 Hz), 4.94-4.82 (2H, m), 4.46 (2H, dd,J=14.6, 6.2 Hz), 4.30 (2H, dd, J=14.6, 5.8 Hz), 3.78 (6H, s), 3.04-2.82(4H, m), 1.26 (18H, s).

Reference Example 6(2R)-N-(4-methoxybenzyl)-3-mercapto-2-t-butoxycarbonylaminopropanamide

[1255]

[1256] The compound prepared in Reference Example 5 (315 mg),tributylphosphine (103 mg) and acetic acid (15 drops) were dissolved ina mixture of dioxane (8 ml) and water (2 ml). The mixture was stirredfor 3 days at room temperature. The reaction mixture was concentrated.The residue was purified by silica gel column chromatography (ethylacetate:chloroform=1:19) to give the title compound (242 mg) having thefollowing physical data.

[1257] TLC: Rf 0.47 (ethyl acetate:chloroform=1:4);

[1258] NMR (CDCl₃): δ 7.24-7.16 (2H, m), 6.90-6.82 (2H, m), 6.70-6.51(1H, m), 5.41 (1H, d, J=7.6 Hz), 4.49-4.29 (3H, m), 3.80 (3H, s), 3.14(1H, ddd, J=14.0, 7.8, 4.4 Hz), 2.73 (1H, ddd, J=14.0, 10.2, 5.8 Hz),1.59-1.50 (1H, m), 1.43 (9H, s).

Example 10(2R)-N-(4-methoxybenzyl)-3-(tetrahydropyran-2-yl)methylthio-2-t-butoxycarbonylaminopropanamide

[1259]

[1260] A solution of the compound prepared in Reference Example 6 (103mg), 2-(bromomethyl)tetrahydropyran (0.05 ml) and potassium carbonate(168 mg) in DMF (5 ml) was degassed and stirred for 15 hours at roomtemperature. The reaction mixture was concentrated. The residue wasdiluted with 1 N hydrochloric acid and extraced with ethyl acetate. Theextract was washed with water and saturated aqueous sodium chloride,successively, dried over anhydrous magnesium sulfate. The organic layerwas concentrated and the residue was purified by silica gel columnchromatography (ethyl acetate:hexane=1:6) to give the compound of thepresent invention (68 mg) having the following physical data.

[1261] TLC: Rf 0.40 (ethyl acetate:chloroform=1:4);

[1262] NMR (CDCl₃): δ 7.28-7.20 (2H, m), 7.09-6.95 (1H, m), 6.90-6.82(2H, m), 5.88-5.78 (1H, m), 4.42-4.38 (2H, m), 4.32-4.20 (1H, m),3.96-3.76 (4H, m), 3.52-3.18 (2H, m), 3.13-3.01 (1H, m), 2.84-2.51 (3H,m), 1.88-1.74 (1H, m), 1.65-1.08 (14H, m).

Example 10(1)˜Example 10(11)

[1263] By the same desired procedure as Example 10, using the compoundprepared in Reference Example 6, the following compounds of the presentinvention were obtained.

Example 10(1)(2R)-N-(4-methoxybenzyl)-3-(bicyclo[2.2.1]heptan-2-ylmethylthio)-2-t-butoxycarbonylaminopropanamide

[1264]

[1265] TLC: Rf 0.81 (ethyl acetate:chloroform=1:4);

[1266] NMR (CDCl₃): δ 7.25-7.18 (2H, m), 6.90-6.82 (2H, m), 6.68-6.58(1H, m), 5.35 (1H, d, J=6.6 Hz), 4.40 (2H, d, J=6.0 Hz), 4.29-4.19 (1H,m), 3.80 (3H, s), 3.05-2.94 (1H, m), 2.90-2.78 (1H, m), 2.65-2.25 (2H,m), 2.24-0.60 (20H, m).

Example 10(2)(2R)-N-(4-methoxybenzyl)-3-(4-methoxycyclohexylmethylthio)-2-t-butoxycarbonylaminopropanamide

[1267]

[1268] (The relative configuration of cyclohexyl ring substituted bymethoxy group is not determined, but the above compound is a singlecompound. This compound is the isomer of the compound prepared inExample 10(3).) less polar

[1269] TLC: Rf 0.41 (ethyl acetate:chloroform=1:4);

[1270] NMR (CDCl₃): δ 7.25-7.17 (2H, m), 6.89-6.82 (2H, m), 6.62 (1H, t,J=5.4 Hz), 5.34 (1H, d, J=7.2 Hz), 4.39 (2H, d, J=5.8 Hz), 4.28-4.18(1H, m), 3.79 (3H, s), 3.44-3.37 (1H, m), 3.29 (3H, s), 2.99 (1H, dd,J=14.0, 6.0 Hz), 2.82 (1H, dd, J=14.0, 7.0 Hz), 2.53-2.37 (2H, m),1.94-1.80 (2H, m), 1.68-1.20 (16H, m).

Example 10(3)(2R)-N-(4-methoxybenzyl)-3-(4-methoxycyclohexylmethylthio)-2-t-butoxycarbonylaminopropanamide

[1271]

[1272] (The relative configuration of cyclohexyl ring substituted bymethoxy group is not determined, but the above compound is a singlecompound. This compound is the isomer of the compound prepared inExample 10(2).) more polar

[1273] TLC: Rf 0.38 (ethyl acetate:chloroform=1:4);

[1274] NMR (CDCl₃): δ 7.25-7.17 (2H, m), 6.89-6.82 (2H, m), 6.62 (1H, t,J=5.0 Hz), 5.34 (1H, d, J=7.8 Hz), 4.39 (2H, d, J=5.8 Hz), 4.28-4.18(1H, m), 3.80 (3H, s), 3.34 (3H, s), 3.14-2.93 (2H, m), 2.83 (1H, dd,J=13.8, 6.6 Hz), 2.47 (1H, dd, J=2.8, 7.0 Hz), 2.40 (1H, dd, J=12.8, 6.8Hz), 2.13-1.98 (2H, m), 1.85-1.81 (2H, m), 1.54-0.84 (14H, m).

Example 10(4)(2R)-N-(4-methoxybenzyl)-3-(1-methylpeperidin-2-ylmethylthio)-2-t-butoxycarbonylaminopropanamide

[1275]

[1276] TLC: Rf 0.45 (methanol:chloroform=1:9);

[1277] NMR (CDCl₃): δ 7.27-7.13 (2.5H, m), 6.89-6.74 (2.5H, m), 6.05(0.5H, d, J=6.8 Hz), 5.69 (0.5H, d, J=7.0 Hz), 4.49-4.15 (3H, m), 3.80(3H, s), 3.15-1.18 (25H, m).

Example 10(5)(2R)-N-(4-methoxybenzyl)-3-(pyridin-4-ylmethylthio)-2-t-butoxycarbonyl-aminopropanamide

[1278]

[1279] TLC: Rf 0.12 (ethyl acetate:chloroform=1:4);

[1280] NMR (CDCl₃): δ 8.54-8.51 (2H, m), 7.27-7.17 (4H, m), 6.89-6.82(2H, m), 6.58 (1H, t, J=5.4 Hz), 5.30 (1H, d, J=7.6 Hz), 4.39 (2H, d,J=5.4 Hz), 4.32-4.22 (1H, m), 3.79 (3H, s), 3.70 (1H, d, J=13.8 Hz),3.62 (1H, d, J=13.8 Hz), 2.89 (1H, dd, J=14.0, 5.6 Hz), 2.76 (1H, dd,J=14.0, 6.6 Hz), 1.43 (9H, s).

Example 10(6)(2R)-N-(4-methoxybenzyl)-3-(quinolin-2-ylmethylthio)-2-t-butoxycarbonyl-aminopropanamide

[1281]

[1282] TLC: Rf 0.50 (ethyl acetate:chloroform=1:4);

[1283] NMR (CDCl₃): δ 8.13 (1H, d, J=8.4 Hz), 7.94 (1H, d, J=8.2 Hz),7.80 (1H, dd, J=8.0, 1.4 Hz), 7.68-7.43 (3H, m), 7.17-7.10 (2H, m),7.05-6.90 (1H, m), 6.82-6.74 (2H, m), 6.19 (1H, d, J=7.8 Hz), 4.51-4.36(2H, m), 4.30 (1H, dd, J=11.4, 5.4 Hz), 4.06 (2H, s), 3.78 (3H, s), 2.96(1H, dd, J=14.4, 6.6 Hz), 2.79 (1H, dd, J=14.4, 5.8 Hz), 1.43 (9H, s).

Example 10(7)(2R)-N-(4-methoxybenzyl)-3-(imidazol-4-ylmethylthio)-2-t-butoxycarbonyl-aminopropanamide

[1284]

[1285] TLC: Rf 0.61 (methanol:chloroform=1:9)

[1286] NMR (CDCl₃): δ 7.63 (1H, br. s), 7.34 (1H, s), 7.24-7.18 (2H, m),6.90-6.81 (2H, m), 5.81 (1H, dd, J=7.6 Hz), 4.46-4.30 (3H, m), 3.82-3.66(5H, m), 2.96 (1H, d, J=14.2, 5.4 Hz), 2.78 (1H, dd, J=14.2, 7.2 Hz),1.44 (9H, s).

Example 10(8)(2R)-N-(4-methoxybenzyl)-3-((1R,4R,5R)-bicyclo[2.2.1]hept-2-en-5-ylmethylthio)-2-t-butoxycarbonylaminopropanamide

[1287]

[1288] TLC: Rf 0.25 (ethyl acetate:chloroform=1:19);

[1289] NMR (CDCl₃): δ 7.27-7.16 (2H, m), 6.92-6.82 (2H, m), 6.67-6.55(1H, m), 6.17 (1H, dd, J=6, 3 Hz), 5.92 (1H, dd, J=6, 3 Hz), 5.33 (1H,d, J=7 Hz), 4.39 (2H, d, J=6 Hz), 4.29-4.16 (1H, m), 3.81 (3H, s), 2.98(1H, dd, J=14, 6 Hz), 2.91-2.75 (3H, m), 2.38-2.14 (3H, m), 1.98-1.82(1H, m), 1.55-1.38 (1H, m), 1.45 (9H, s), 1.29-1.21 (1H, m), 0.63-0.52(1H, m).

Example 10(9)(2R)-N-(4-methoxybenzyl)-3-((1S,4S,5S)-bicyclo[2.2.1]hept-2-en-5-ylmethylthio)-2-t-butoxycarbonylaminopropanamide

[1290]

[1291] TLC: Rf 0.38 (ethyl acetate:hexane=1:2);

[1292] NMR (CDCl₃): δ 7.27-7.17 (2H, m), 6.93-6.81 (2H, m), 6.70-6.55(1H, m), 6.16 (1H, dd, J=6, 3 Hz), 5.94 (1H, dd, J=6, 3 Hz), 5.33 (1H,d, J=7 Hz), 4.39 (2H, d, J=6 Hz), 4.29-4.15 (1H, m), 3.81 (3H, s), 2.96(1H, dd, J=14, 6 Hz), 2.92-2.74 (3H, m), 2.37-2.13 (3H, m), 1.97-1.82(1H, m), 1.55-1.38 (1H, m), 1.44 (9H, s), 1.29-1.20 (1H, m), 0.63-0.51(1H, m).

Example 10(10)(2R)-N-(4-methoxybenzyl)-3-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylmethylthio)-2-t-butoxycarbonylaminopropanamide

[1293]

[1294] TLC: Rf 0.48 (ethyl acetate:hexane=1:2);

[1295] NMR (CDCl₃): δ 7.27-7.17 (2H, m), 6.93-6.83 (2H, m), 6.71-6.57(1H, m), 5.35 (1H, d, J=7 Hz), 4.40 (2H, d, J=6 Hz), 4.32-4.19 (1H, m),3.81 (3H, s), 2.99 (1H, dd, J=14, 6 Hz), 2.86 (1H, dd, J=14, 7 Hz), 2.58(1H, dd, J=12, 8 Hz), 2.55 (1H, dd, J=12, 8 Hz), 2.23-2.13 (2H, m),2.13-1.88 (1H, m), 1.88-1.70 (1H, m), 1.64-1.18 (5H, m), 1.45 (9H, s),1.16-1.01 (1H, m), 0.66 (1H, ddd, J=12, 5, 2 Hz).

Example 10(11)(2R)-N-(4-methoxybenzyl)-3-((1R,2S,4S)-bicyclo[2.2.1]heptan-2-ylmethylthio)-2-t-butoxycarbonylaminopropanamide

[1296]

[1297] TLC: Rf 0.23 (ethyl acetate:hexane=1:3);

[1298] NMR (CDCl₃): δ 7.27-7.16 (2H, m), 6.93-6.81 (2H, m), 6.73-6.57(1H, m), 5.36 (1H, d, J=7 Hz), 4.40 (2H, d, J=6 Hz), 4.31-4.18 (1H, m),3.81 (3H, s), 2.98 (1H, dd, J=14, 6 Hz), 2.87 (1H, dd, J=14, 7 Hz), 2.58(1H, dd, J=12, 8 Hz), 2.55 (1H, dd, J=12, 8 Hz), 2.24-2.13 (2H, m),2.10-1.88 (1H, m), 1.87-1.69 (1H, m), 1.60-1.20 (5H, m), 1.43 (9H, s),1.16-1.01 (1H, m), 0.66 (1H, ddd, J=12, 5, 2 Hz).

Reference Example 7 (2S)-4-hydroxy-2-t-butoxycarbonylaminobutanoicacid.4-methoxybenzyl ester

[1299]

[1300] Under cooling with ice, isobutyl chloroformate (0.35 ml) wasadded dropwise to a solution of(2S)-3-carboxy-2-t-butoxycarbonylaminopropanoic acid.4-methoxybenzylester-dicyclohexylamine salt (1350 mg) and N-methylmorpholine (0.32 ml)in tetrahydrofuran (6 ml). The mixture was stirred for 45 minutes. Thereaction mixture was filtered through Celite. Under cooling with ice,sodium borohydride (229 mg) was added to the filtrate and methanol (1.2ml) was added dropwise thereto for 1 hour. One normal hydrochloric acidwas added to the reaciton mixture. The mixture was extracted with ethylacetate. The extract was washed with water and saturated aqueous sodiumchloride, successively, and concentrated. The residue was purified bysilica gel column chromatography (ethyl acetate hexane=1:2) to give thetitle compound (180 mg) having the following physical data.

[1301] TLC: Rf 0.42 (methanol:chloroform=1:9);

[1302] NMR (CDCl₃): δ 7.30 (2H, d, J=8.7 Hz), 6.89 (2H, d, J=8.7 Hz),5.38 (1H, brd, J=8.4 Hz), 5.13 (2H, s), 4.55-4.43,(1H, m), 3.82 (3H, s),3.75-3.55 (2H, m), 3.24-3.05 (1H, m), 2.23-2.06 (1H, m), 1.69-1.56 (1H,m).

Reference Example 8 (2S)-3-formyl-2-t-butoxycarbonylaminopropanoicacid.4-methoxybenzyl ester

[1303]

[1304] The compound prepared in Reference Example 7 (162 mg) andtriethylamine (0.40 ml) were dissolved in a mixture of methylenechloride (4 ml) and dimethylsulfoxide (4 ml). Under cooling with ice,sulfur trioxide pyridine complex (228 mg) was added to the mixure. Themixture was warmed to room temperature. The reaction mixture was dilutedwith water and extracted with ethyl acetate. The extract was washed with1N hydrochloric acid, water and saturated aqueous sodium chloride,successively, dried over anhydrous magnesium sulfate and concentrated.The obtained title compound (180 mg) was used for the next reactionwithout purification.

Example 11 (2S)-4-cyclopentylamino-2-t-butoxycarbonylaminobutanoicacid.4-methoxybenzyl ester

[1305]

[1306] Under cooling with ice, sodium cyanoborohydride (74 mg) was addedto a solution of the compound prepared in Reference Example 8 (180 mg),cyclopentylamine (0.10 ml) and acetic acid (0.04 ml) in methanol (5 ml).The mixture was stirred for 6.5 hours under cooling with ice and stirredfor 12 hours at room temperature. The reaction mixture was diluted withwater and methanol was distilled off under reduced pressure. The aqueouslayer was extracted with ethyl acetate. The extract was washed withwater and saturated aqueous sodium chloride, successively, dried overanhydrous magnesium sulfate. The organic layer was concentrated and theresidue was purified by silica gel column chromatography (ethylacetate:hexane=1:1) to give the compound of the present invention (35mg) having the following physical data.

[1307] TLC: Rf 0.17 (methanol:chloroform=1:9);

[1308] NMR (CD₃OD): δ 7.31 (2H, d, J=8.4 Hz), 6.89 (2H, d, J=8.4 Hz),5.17 (1H, d, J=11.8 Hz), 5.04 (1H, d, J=11.8 Hz), 4.26-4.14 (1H, m),3.78 (3H, s), 3.27-3.12 (1H, m), 2.77 (2H, t, J=6.2 Hz), 2.12-1.49 (10H,m), 1.42 (9H, s).

Example 12(2S)-N-(4-methoxybenzyl)-3-cyclohexylsulfonylamino-2-t-butoxycarbonyl-aminopropanamide

[1309]

[1310](2S)-N-(4-methoxybenzyl)-3-amino-2-t-butoxycarbonylaminopropanamide (98mg) was dissolved in a mixture of pyridine (3 ml) and methylene chloride(5 ml). Under cooling with ice, cyclohexylsulfonyl chloride (166 mg) wasadded thereto and dimethylaminopyridine (3 mg) was added thereto. Themixture was stirred for 1 hour. The reaction mixture was diluted withwater and extracted with ethyl acetate. The extract was washed with 1Nhydrochloric acid, water and saturated aqueous sodium chloride,successively, dried over anhydrous magnesium sulfate. The organic layerwas concentrated and the residue was purified by silica gel columnchromatography (ethyl acetate:hexane=1:2) to give the compound of thepresent invention (25 mg) having the following physical data.

[1311] TLC: Rf 0.43 (ethyl acetate:hexane=1:1);

[1312] NMR (CDCl₃): δ 7.22-7.14 (2H, m), 7.12-7.00 (1H, m), 6.89-6.81(2H, m), 5.75 (1H, d, J=7.2 Hz), 5.34-5.20 (1H, m), 4.46-4.21 (3H, m),3.79 (3H, s), 3.60 (1H, dt, J=14.0, 4.8 Hz), 3.38 (1H, ddd, J=14.0,8.6,4.2 Hz), 2.97-2.82 (1H, m), 2.24-1.08 (19H, m).

Reference Example 9(2R)-2-t-butoxycarbonylamino-2-(4-methoxybenzylcarbomoyl)ethansulfonicacid sodium salt

[1313]

[1314] Under cooling with ice, dicyclohexylcarbodiimide (823 mg) wasadded to a solution of(2R)-2-t-butoxycarbonylamino-2-carboxyethansulfonic acid sodium salt(893 mg) and p-nitrophenol (470 mg) in DMF (15 ml). The mixture wasstirred for 30 minutes. The reaction mixture was allowed to stand for 4days at 5° C. Acetic acid was added to the reaction mixture for treatingwith an excess amount of-dicyclohexylcarbodiimide. The mixture wasfiltered. The filtrate was concentrated. Under cooling with ice,4-methoxybenzylamine (0.40 ml) was added to a solution of the residue inDMF (10 ml). The mixture was stirred for 2 hours. The reaction mixturewas concentrated. The residue was diluted with water. The aqueous layerwas washed with ethyl acetate. The aqueous layer was concentrated underreduced pressure to give the compound of the present invention (610 mg)having the following physical data.

[1315] TLC: Rf 0.33 (methanol:chloroform=1:4);

[1316] NMR (CD₃OD): δ 7.24-7.18 (2H, m), 6.87-6.81 (2H, m), 4.42-4.21(3H, m), 3.75 (3H, s), 3.22-3.16 (2H, m), 1.41 (9H, s).

Example 13(2R)-N-(4-methoxybenzyl)-3-cyclohexylsulfamoyl-2-t-butoxycarbonyl-aminopropanamide

[1317]

[1318] Under cooling with ice, sulfuryl chloride (0.045 ml) was addeddropwise to a solution of triphenylphosphine (127 mg) in methylenechloride (1 ml). The mixture was stirred and allowed to warm to roomtemperature. A solution of the compound prepared in Reference Example 9(100 mg) in methylene chloride (2 ml) was added to the reaction mixture.The mixture was stirred for 1 hour at room temperature. The mixture ofcyclohexylamine (0.14 ml) and triethylamine (0.17 ml) was added to thereaction mixture. The mixture was stirred for 1 hour. The reactionmixture was diluted with saturated aqueous sodium hydrogencarbonate andextracted with chloroform. The extract was washed with 1N hydrochloricacid, water and saturated aqueous sodium chloride, successively, driedover anhydrous magnesium sulfate. The organic layer was concentrated andthe residue was purified by silica gel column chromatography (ethylacetate:hexane=1:2) to give the compound of the present invention (15mg) having the following physical data.

[1319] TLC: Rf 0.56 (ethyl acetate:hexane=1:1);

[1320] NMR (CDCl₃): δ 7.24-7.15 (2H, m), 6.90-6.81 (3H, m), 5.72 (1H, d,J=8.4 Hz), 4.75 (1H, d, J=7.4 Hz), 4.69-4.60 (1H, m), 4.43 (1H, dd,J=14.0, 5.4 Hz), 4.33 (1H, dd, J=14.0, 5.8 Hz), 3.79 (3H, s), 3.60 (1H,dd, J=15.0, 6.2 Hz), 3.50 (1H, dd, J=15.0, 4.8 Hz), 3.38-3.19 (1H, m),2.04-1.08 (19H, m).

Example 13(1) (2R)-N-(4-methoxybenzyl)-3-(piperidin-1-ylsul(2R)-N-(4-methoxybenzyl)-3-(piperidin-1-ylsulfonyl)-2-t-butoxycarbonyl-aminopropanamide

[1321]

[1322] By the same desired procedure as Example 13, using the compoundprepared in Reference Example 9, the compound of the present inventionhaving the following physical data was obtained.

[1323] TLC: Rf 0.41 (ethyl acetate:hexane=1:1);

[1324] NMR (CDCl₃): δ 7.25-7.17 (2H, m), 6.89-6.82 (3H, m), 5.64 (1H, d,J=7.4 Hz), 4.61-4.51 (1H, m), 4.45 (1H, dd, J=15.0, 6.2 Hz), 4.35 (1H,dd, J=15.0, 5.4 Hz), 3.79 (3H, s), 3.54 (1H, dd, J=13.2, 5.8 Hz), 3.39(1H, dd, J=13.2, 5.4 Hz), 3.26-3.21 (4H, m), 1.75-1.50 (6H, m), 1.44(9H, s).

Example 14(2S)-3-cyclohexyloxycarbonyl-2-(N-benzyl-N-t-butoxycarbonylamino)-prpanoicacid.4-methoxybenzyl ester

[1325]

[1326] Under cooling with ice, sodium hydride (60%, 13 mg) was added toa solution of the compound prepared in Example 2(4) (122 mg) in DMF (3ml). The mixture was stirred for 30 minutes at 0° C. Benzyl bromide (37μl) was added to the reaction mixture. The mixture was stirred for 3hours at 0° C. The reaction mixture was acidified by adding 1Nhydrochloric acid, diluted with water and extracted with ethyl acetate.The extract was washed with water and saturated aqueous sodium chloride,successively, dried over anhydrous magnesium sulfate. The organic layerwas concentrated and the residue was purified by silica gel columnchromatography (ethyl acetate:hexane=1:8) to give the compound of thepresent invention (52 mg) having the following physical data.

[1327] TLC: Rf 0.44 (ethyl acetate:hexane=1:4);

[1328] NMR (CDCl₃): δ 7.34-7.14 (7H, m), 6.89-6.82 (2H, m), 5.10-4.25(6H, m), 3.81 (3H, s), 3.25-3.03 (1H, m), 2.72-2.46 (1H, m), 1.84-1.22(19H, m).

Example 15 (2S)-3-cyclohexyloxycarbonyl-2-benzylaminopropanoicacid.4-methoxybenzyl ester

[1329]

[1330] P-toluenesulfonic acid monohydrate (42 mg) was added to asolution of the compound prepared in Example 14 (115 mg) in diethylether(0.5 ml). The mixture was stirred for 19 hours at room temperature. Thereaction mixture was washed with diethylether. The obtained cyrstal wasdissolved in ethyl acetate, washed with saturated aqueous sodiumhydrogencarbonate and saturated aqueous sodium chloride, successively,dried over anhydrous magnesium sulfate and concentrated to give thecompound of the present invention (89 mg) having the following physicaldata.

[1331] TLC: Rf 0.63 (ethyl acetate:hexane=1:2);

[1332] NMR (CDCl₃): δ 7.34-7.22 (7H, m), 6.93-6.85 (2H, m), 5.11 (2H,s), 4.80-4.66 (1H, m), 3.85 (1H, d, J=12.8 Hz), 3.81 (3H, s), 3.69 (1H,d, J=12.8 Hz), 3.68 (1H, dd, J=6.8, 6.2 Hz), 2.73 (1H, dd, J=15.8, 6.2Hz), 2.63 (1H, dd, J=15.8, 6.8 Hz), 1.95 (1H, br. s), 1.84-1.19 (10H,m).

Example 16(2R)-N-(4-phenoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-thiazolidin-4-ylcarbonylamino)propanamide

[1333]

[1334] A solution of the compound prepared in Example 9(13) (107 mg) inethyl acetate (10 ml) was washed with saturated aqueous sodiumhydrogencarbonate (5 ml) and saturated aqueous sodium chloride,successively, dried over anhydrous magnesium sulfate and concentrated togive the compound of the present invention (96 mg) having the followingphysical data.

[1335] TLC: Rf 0.39 (ethyl acetate:hexane=1:1);

[1336] NMR (CDCl₃): δ 7.88 (d, J=7.5 Hz, 1H), 7.37-7.30 (m, 2H),7.25-7.21 (m, 2H), 7.14-7.08 (m, 1H), 7.02-6.94 (m, 4H), 6.84-6.80 (m,1H), 4.49-4.36 (m, 3H), 4.26 (d, J=9.9 Hz, 1H), 4.19-4.15 (m, 1H), 4.05(d, J=9.9 Hz, 1H), 3.42 (dd, J=11.1, 4.2 Hz, 1H), 3.10 (dd, J=11.1, 7.5Hz, 1H), 2.93 (dd, J=13.8, 6.3 Hz, 2H), 2.83 (dd, J=13.8, 7.2 Hz, m),2.45 (d, J=6.6 Hz, 2H), 1.86-1.58 (m, 5H), 1.51-1.36 (m, 1H), 1.29-1.05(3H, m), 0.98-0.85 (m, 2H).

Example 16(1)(2R)-N-(1-phenylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-thiazolidin-4-ylcarbonylamino)propanamide

[1337]

[1338] By the same desired procedure as Example 16, using the compoundprepared in Example 9(16), the compound of the present invention havingthe following physical data was obtained.

[1339] TLC: Rf 0.26 (hexane:ethyl acetate=1:1)

[1340] NMR (CDCl₃): δ 7.86 (d, J=7.5 Hz, 1H), 7.29-7.23 (m, 2H),6.95-6.91 (m, 2H), 6.88-6.83 (m, 1H), 6.47 (d, J=8.1 Hz, 1H), 4.37 (dd,J=14.1, 7.5 Hz, 1H), 4.27 (d, J=9.9 Hz, 1H), 4.18 (dd, J=7.8, 4.2 Hz,1H), 4.05 (d, J=9.9 Hz, 1H), 4.00-3.88 (m, 1H), 3.63-3.51 (m, 2H), 3.43(dd, J=11.1, 4.2 Hz, 1H), 3.12 (dd, J=11.1, 7.8 Hz, 1H), 2.95-2.86 (m,3H), 2.79 (dd, J=13.8, 7.5 Hz, 1H), 2.48 (d, J=6.9 Hz, 2H), 2.08-1.98(m, 2H), 1.84-1.39 (m, 8H), 1.31-1.06 (m, 3H), 1.00-0.87 (m, 2H).

Example 17˜Example 17(16)

[1341] By the same desired procedure as Example 9→Example 16, using thecomounds prepared in Example 6(36), Example 6(44), Example 6(49),Example 6(60), Example 6(61), Example 6(69), Example 6(74)˜Example 6(83)and Example 6(86), the following compounds of the present invention wereobtained.

Example 17(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((2RS)-thiazolidin-2-ylcarbonylamino)propanamide

[1342]

[1343] TLC: Rf 0.45 (methylene chloride:methanol=19:1);

[1344] NMR (CD₃OD): δ 7.27-7.17 (2H, m), 6.92-6.82 (2H, m), 5.01 and4.98 (1H, s), 4.49 and 4.48 (1H, t, J=7 Hz), 4.34 (1H, d, J=15 Hz), 4.28(1H, d, J=15 Hz), 3.77 (3H, s), 3.48-3.02 (2H, m), 3.00-2.71 (4H, m),2.41 and 2.39 (2H, d, J=7 Hz), 1.90-0.78 (11H, m).

Example 17(1)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-thiazolidin-4-ylcarbonylamino)propanamide

[1345]

[1346] TLC: Rf 0.59 (methylene chloride:methanol=9:1);

[1347] NMR (CDCl₃): δ 7.87 (1H, d, J=8 Hz), 7.25-7.18 (2H, m), 6.90-6.83(2H, m), 6.78-6.70 (1H, m), 4.48-4.31 (3H, m), 4.30-4.21 (1H, m),4.20-4.12 (1H, m), 4.10-4.00 (1H, m), 3.80 (3H, s), 3.41 (1H, dd, J=11,4 Hz), 3.10 (1H, dd, J=11, 8 Hz), 2.92 (1H, dd, J=14, 6 Hz), 2.83 (1H,dd, J=14, 7 Hz), 2.50-2.38 (1H, b), 2.44 (2H, d, J=7 Hz), 1.85-1.55 (5H,m), 1.50-1.35 (1H, m), 1.31-1.03 (3H, m), 0.98-0.84 (2H, m).

Example 17(2)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(2-aminothiazol-4-ylcarbonylamino)propanamide

[1348]

[1349] TLC: Rf 0.30 (methylene chloride:methanol=19:1);

[1350] (CDCl₃+3drops of CD₃OD) δ 7.33 (1H, s), 7.27-7.17 (2H, m),6.90-6.80 (2H, m), 4.64 (1H, t, J=6 Hz), 4.41 (1H, d, J=15 Hz), 4.35(1H, d, J=15 Hz), 3.80 (3H, s), 3.08-2.84 (2H, m), 2.44 (2H, d, J=7 Hz),1.87-0.78 (11H, m).

Example 17(3)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(thiazolidin-2-ylcarbonylamino)propanamide

[1351]

[1352] (The absolute configuration of * carbon is not determined, butthe above compound is a single optical isomer.)

[1353] [α]_(D)=−71.7 (c 0.21, CHCl₃);

[1354] TLC: Rf 0.27 (hexane:ethyl acetate=1:2);

[1355] NMR (CDCl₃): δ 7.65 (1H, d, J=7.4 Hz), 7.21 (2H, d, J=8.8 Hz),6.86 (2H, d, J=8.8 Hz), 6.80-6.73 (1H, br), 4.99 (1H, s), 4.50-4.38 (3H,m), 3.80 (3H, s), 3.51-3.40 (1H, m), 3.15-2.94 (3H, m), 2.88-2.75 (2H,m), 2.44 (2H, d, J=7.0 Hz), 1.83-1.30 (6H, m), 1.28-0.78 (5H, m).

Example 17(4)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(thiazolidin-2-ylcarbonylamino)propanamide

[1356]

[1357] (The absolute configuration of * carbon is not determined, butthe above compound is a single optical isomer.)

[1358] [α]_(D)=+51.5 (c 0.19, CHCl₃);

[1359] TLC: Rf 0.16 (hexane:ethyl acetate=1:2);

[1360] NMR (CDCl₃): δ 7.69 (1H, d, J=7.0 Hz), 7.21 (2H, d, J=8.8 Hz),6.86 (2H, d, J=8.8 Hz), 6.81-6.69 (1H, br), 5.01 (1H, s), 4.51-4.37 (3H,m), 3.80 (3H, s), 3.52-3.39 (1H, m), 3.08-2.91 (3H, m), 2.89-2.73 (2H,m), 2.53-2.40 (2H, m), 1.83-1.37 (6H, m), 1.34-0.79 (5H, m).

Example 17(5)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((2RS,4R)-2-(2-methylpropyl)thiazolidin-4-ylcarbonylamino)propanamide

[1361]

[1362] TLC: Rf 0.41 (methanol:methylene chloride=1:19);

[1363] NMR (CD₃OD): δ 7.25-7.18 (2H, m), 6.89-6.82 (2H, m), 4.61-4.46(2H, m), 4.39-4.24 (2H, m), 4.39-4.24 (m) and 3.84 (t, J=8 Hz) (1H),3.76 (3H, s), 3.39 (dd, J=10, 3 Hz) and 3.19 (dd, J=10, 8 Hz) (1H), 3.09(dd, J=10, 8 Hz) and 2.99-2.90 (m) (1H), 2.90-2.76 (2H, m), 2.38 and2.41 (2H, d, J=6 Hz), 1.90-1.55 (8H, m), 1.49-1.33 (1H, m), 1.33-1.06(3H, m), 1.06-0.83 (8H, m).

Example 17(6)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((2RS,4R)-2-phenylthiazolidin-4-ylcarbonylamino)propanamide

[1364]

[1365] TLC: Rf 0.43 (methanol:methylene chloride=1:19);

[1366] NMR (CDCl₃+5 drops of CD₃OD): δ 7.57-7.48 (m, 2H), 7.45-7.33 (m,3H), 7.25-7.18 (m, 2H), 6.90-6.83 (m, 2H), 5.60 and 5.53 (s, 1H),4.53-4.29 and 3.99-3.90 (m, 4H), 3.79 (s, 3H), 3.43-3.35 (m) and 3.64(dd, J=11, 3 Hz) (1H), 3.19 and 3.39 (dd, J=11, 8 Hz, 1H), 2.73 and 2.92(d, J=7 Hz, 2H), 2.40 and 2.43 (d, J=7 Hz, 2H), 1.85-1.58 (m, 5H),1.51-1.34 (m, 1H), 1.31-1.03 (m, 3H), 1.00-0.80 (m, 2H).

Example 17(7)(4R)-N-((1R)-2-cyclohexylmethylthio-1-(4-phenylpiperazin-1-ylcarbonyl)ethyl)-thiazolidin-4-ylcarboxamide

[1367]

[1368] TLC: Rf 0.55 (methanol:chloroform=1:9);

[1369] NMR (CDCl₃): δ 7.85 (d, J=8.7 Hz, 1H), 7.32-7.26 (m, 2H),6.94-6.89 (m, 3H), 5.12-5.04 (m, 1H), 4.27 (d, J=9.9 Hz, 1H), 4.15 (dd,J=7.5, 4.2 Hz, 1H), 4.07 (d, J=9.9 Hz, 1H), 3.89-3.74 (m, 4H), 3.44 (dd,J=10.8, 4.2 Hz, 1H), 3.32-3.09 (m, 5H), 2.91 (dd, J=13.5, 3.9 Hz, 1H),2.76 (dd, J=13.5, 6.3 Hz, 1H), 2.54-2.34 (m, 3H), 1.86-1.60 (m, 5H),1.50-1.35 (m, 1H), 1.30-1.04 (m, 3H), 1.02-0.84 (m, 2H).

Example 17(8)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((3RS)-thiomorpholin-3-ylcarbonylamino)propanamide

[1370]

[1371] TLC: Rf 0.31 and 0.27 (methylene chloride:methanol=19:1);

[1372] NMR (CD₃OD): δ 7.26-7.18 (m, 2H), 6.88-6.83 (m, 2H), 4.54-4.46(m, 1H), 4.38-4.24 (m, 2H), 3.76 (s, 3H), 3.60-3.52 (m, 1H), 3.36-3.28(m, 1H), 3.02-2.60 (m, 6H), 2.44-2.32 (m, 3H), 1.86-1.60 (m, 5H),1.50-1.34 (m, 1H), 1.34-1.07 (m, 3H), 1.00-0.83 (m, 2H).

Example 17(9)(2R)-N-(4-phenoxybenzyl)-3-cyclohexylmethylthio-2-((3RS)-thiomorpholin-3-ylcarbonylamino)propanamide

[1373]

[1374] TLC: Rf 0.14 and 0.16 (methylene chloride:methanol=19:1);

[1375] NMR (CDCl₃): δ 7.69 and 7.62 (d, J=8 Hz, 1H), 7.38-7.30 (m, 2H),7.28-7.21 (m, 2H), 7.15-7.08 (m, 1H), 7.03-6.93 (m, 4H), 6.91-6.77 (m,1H), 4.54-4.35 (m, 4H), 3.60-3.51 (m, 1H), 3.38-3.23 (m, 1H), 3.10-2.90(m, 2H), 2.88-2.76 (m, 2H), 2.75-2.37 (m, 5H), 1.86-1.52 (m, 5H),1.52-1.35 (m, 1H), 1.30-1.04 (m, 3H), 1.00-0.84 (m, 2H).

Example 17(10)(2R)-N-(2-phenoxypyridin-5-yl)-3-cyclohexylmethylthio-2-((4R)-thiazolidin-4-ylcarbonylamino)propanamide

[1376]

[1377] TLC: Rf 0.18 (methanol:chloroform=1:19);

[1378] NMR (CDCl₃): δ 8.94-8.82 (m, 1H), 8.23 (d, J=2.4 Hz, 1H),8.05-8.00 (m, 2H), 7.42-7.35 (m, 2H), 7.21-7.16 (m, 1H), 7.12-7.07 (m,2H), 6.86 (d, J=8.7 Hz, 1H), 4.64-4.57 (m, 1H), 4.30 (d, J=9.9 Hz, 1H),4.29-4.26 (m, H), 4.07 (d, J=9.9 Hz, 1H), 3.48 (dd, J=10.8, 3.3 Hz, 1H),3.14 (dd, J=10.8, 8.1, 1H), 3.00 (dd, J=13.8, 7.2 Hz, 1H), 2.92 (dd,J=13.8, 6.9 Hz, 1H), 2.48 (d, J=6.6 Hz, 2H), 1.88-1.60 (m, 5H),1.54-1.39 (m, 1H), 1.32-1.04 (m, 3H), 1.01-0.84 (m, 2H).

Example 17(11)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((2RS)-thiomorpholin-2-ylcarbonylamino)propanamide

[1379]

[1380] TLC: Rf 0.46 and 0.41 (methylene chloride:methanol=9:1);

[1381] NMR (CDCl₃): δ 8.92 and 8.62 (d, J=8 Hz, 1H), 7.25-7.17 (m, 2H),6.90-6.82 (m, 2H), 4.66-4.52 (m, 1H), 4.48-4.29 (m, 2H), 3.79 (s, 3H),3.61-3.53 (m, 1H), 3.31-2.81 (m, 7H), 2.55-2.40 (m, 2H), 2.36-2.24 (m,1H), 1.86-1.58 (m, 5H), 1.53-1.35 (m, 1H), 1.31-1.04 (m, 3H), 1.00-0.83(m, 2H).

Example 17(12)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((4RS)-1,3-perhydrothiazin-4-ylcarbonylamino)propanamide

[1382]

[1383] TLC: Rf 0.22 and 0.19 (methylene chloride:methanol=49:1);

[1384] NMR (CDCl₃): δ 7.66-7.56 (m, 1H), 7.24-7.16 (m, 2H), 6.90-6.82(m, 2H), 6.78-6.65 (m, 1H), 4.52-4.41 (m, 1H), 4.41-4.30 (m, 2H),4.17-4.01 (m, 2H), 3.80 (s, 3H), 3.36-3.28 (m, 1H), 2.99-2.73 (m, 4H),2.49-2.42 (m, 2H), 2.31-2.20 (m, 1H), 1.85-1.35 (m, 7H), 1.30-1.03 (m,3H), 1.00-0.83 (m, 2H).

Example 17(13)(2R)-N-(2-phenoxypyridin-5-ylmethyl)-3-cyclohexylmethylthio-2-((4R)-thiazolidin-+B4-ylcarbonylamino)propanamide

[1385]

[1386] TLC: Rf 0.41 (methanol:chloroform=1:19);

[1387] NMR (CDCl₃): δ 8.09 (d, J=2.1 Hz, 1H), 7.87 (d, J=7.5 Hz, 1H),7.64 (dd, J=8.4, 2.4 Hz, 1H), 7.43-7.37 (m, 2H), 7.20 (it, J=7.2, 1.2Hz, 1H), 7.14-7.09 (m, 2H), 6.94 (t, J=6.0 Hz, 1H), 6.87 (d, J=8.4 Hz,1H), 4.43 (dd, J=13.8, 7.2, 1H), 4.40 (d, J=6.0 Hz, 2H), 4.27 (d, J=9.9Hz, 1H), 4.18 (dd, J=7.8, 4.2 Hz, 1H), 4.04 (d, J=9.9 Hz, 1H), 3.42 (dd,J=11.1, 3.9 Hz, 1H), 3.10 (dd, J=11.1, 7.8 Hz, 1H), 2.92 (dd, J=13.8,6.6 Hz, 1H), 2.82 (dd, J=13.8, 7.2 Hz, 1H), 2.43 (d, J=9.3 hz, 2H),1.86-1.58 (m, 5H), 1.48-1.35 (m, 1H), 1.30-1.04 (m, 3H), 0.98-0.82 (m,2H).

Example 17(14)(2R)-N-(4-(morpholin-4-yl)benzyl)-3-cyclohexylmethylthio-2-((4R)-thiazolidin-4-ylcarbonylamino)propanamide

[1388]

[1389] TLC: Rf 0.46 (methanol:chloroform=1:19);

[1390] NMR (CDCl₃): δ 7.86 (d, J=7.5 Hz, 1H), 7.21-7.16 (m, 2H),6.89-6.84 (m, 2H), 6.71 (t, J=5.1 Hz, 1H), 4.44 (dd, J=13.8, 6.9 Hz,1H), 4.40 (dd, J=14.7, 5.7 Hz, 1H), 4.34 (dd, J=14.7, 5.4 Hz, 1H), 4.26(d, J=9.9 Hz, 1H), 4.14 (dd, J=7.5, 3.9 Hz, 1H), 4.04 (d, J=9.9 Hz, 1H),3.87-3.84 (m, 4H), 3.40 (dd, J=11.1, 4.2 Hz, 1H), 3.16-3.12 (m, 4H),3.09 (dd, J=11.1, 7.8 Hz, 1H), 2.92 (dd, J=13.8, 6.3 Hz, 1H), 2.82 (dd,J=13.8, 7.2 Hz, 1H), 2.43 (d, J=6.9 Hz, 2H), 1.85-1.58 (m, 5H),1.51-1.35 (m, 1H), 1.30-1.04 (m, 3H), 0.98-0.82 (m, 2H).

Example 17(15)(2R)-N-(4-phenoxybenzyl)-3-cyclohexylmethylthio-2-((4RS)-1,3-perhydrothiazin-4-ylcarbonylamino)propanamide

[1391]

[1392] TLC: Rf 0.39 and 0.30 (methylene chloride:methanol=19:1),

[1393] NMR (CDCl₃): δ 7.68-7.56 (m, 1H), 7.38-7.29 (m, 2H), 7.29-7.20(m, 2H), 7.14-7.07 (m, 1H), 7.05-6.90 (m, 4H), 6.87-6.82 (m, 1H),4.54-4.34 (m, 3H), 4.18-4.00 (m, 2H), 3.37-3.29 (m, 1H), 3.00-2.74 (m,4H), 2.50-2.43 (m, 2H), 2.32-2.20 (m, 1H), 1.86-1.35 (m, 8H), 1.31-1.03(m, 3H), 1.03-0.83 (m, 2H).

Example 17(16)(2R)-N-(1-methylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-thiazolidin-4-ylcarbonylamino)propanamide

[1394]

[1395] TLC: Rf 0.24 (chloroform:methanol=9:1);

[1396] NMR (CD₃OD): δ 4.46-4.39 (m, 1H), 4.23-4.09 (m, 3H), 3.75-3.64(m, 1H), 3.23 (dd, J=10.2, 4.4 Hz, 1H), 3.03 (dd, J=10.2, 7.2 Hz, 1H),2.93-2.70 (m, 4H), 2.43 (d, J=6.6 Hz, 2H), 2.27 (s, 3H), 2.22-2.06 (m,2H), 1.94-1.10 (m, 13H), 1.03-0.82 (m, 2H).

Example 18(2R)-N-((1R)-1-(4-nitrophenyl)ethyl)-3-cyclohexylmethylthio-2-((4R)-3-(2-methylpropylcarbonyl)thiazolidin-4-ylcarbonylamino)propanamide

[1397]

[1398] Under cooling with ice, isovaleryl chloride (0.025 ml) was addedto a solution of the compound prepared in Example 9(6) (98 mg) andtriethylamine (0.06 ml) in methylene chloride (3 ml). The mixture wasstirred for 1 hour. The reaction mixture was washed with saturatedaqueous sodium hydrogencarbonate, 1N hydrochloric acid, water andsaturated aqueous sodium chloride, successively, dried over anhydrousmagnesium sulfate. The organic layer was concentrated and the residuewas purified by silica gel column chromatography (ethylacetate:hexane=1:2) to give the compound of the present invention (81mg) having the following physical data.

[1399] TLC: Rf 0.48 (ethyl acetate:hexane=1:1);

[1400] NMR (CDCl₃): δ 8.16 (2H, d, J=8.8 Hz), 7.56 (2H, d, J=8.8 Hz),7.45 (1H, d, J=7.6 Hz), 6.95 (1H, d, J=8.2 Hz), 5.20-5.06 (1H, m), 4.87(1H, t, J=5.6 Hz), 4.66-4.56 (3H, m) 3.33 (2H, d, J=5.6 Hz), 3.23 (1H,dd, J=13.8, 4.0 Hz), 2.75 (1H, dd, J=13.8, 5.8 Hz), 2.34 (2H, d, J=7.0Hz), 2.24-2.01 (3H, m), 1.72-0.60 (20H, m).

Example 18(1)˜Example 18(5)

[1401] By the same desired procedure as Example 18, using the compoundsprepared in Example 16, Example 17 and Example 17(1), the followingcompouns of the present invention were obtained.

Example 18(1)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((2RS)-3-acetylthiazolidin-2-ylcarbonylamino)propanamide

[1402]

[1403] TLC: Rf 0.40 (ethyl acetate)

[1404] NMR (CDCl₃): δ 7.46 (1H, t, J=6.2 Hz), 7.27-7.21 (2H, m),6.89-6.77 (3H, m), 5.49-5.29 (1H, m), 4.62-4.34 (3H, m), 4.06-3.94 (1H,m), 3.88-3.72 (4H, m), 3.64-3.00 (3H, m), 2.85-2.74 (1H, m), 2.49-2.27(2H, m), 2.18-2.03 (3H, m), 1.85-0.74 (11H, m).

Example 18(2)(2R)-N-(4-phenoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-methoxycarbonylthiazolidin-4-ylcarbonylamino)propanamide

[1405]

[1406] TLC: Rf 0.39 (hexane:ethyl acetate=1:1);

[1407] NMR (CDCl₃): δ 7.37-6.93 (m, 1 1H), 4.73-4.32 (m, 6H), 3.67 (s,3H), 3.32 (dd, J=12.0, 3.9 Hz, 1H), 3.28 (dd, J=12.0, 6.9 Hz, 1H),3.23-3.01 (br, 1H), 2.82 (dd, J=13.8, 6.6 Hz, 1H), 2.48-2.34 (m, 2H),1.82-1.52 (m, 5H), 1.49-1.04 (m, 4H), 0.96-0.81 (m, 2H).

Example 18(3)(2R)-N-(4-phenoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-(2-methylpropoxycarbonyl)thiazolidin-4-ylcarbonylamino)propanamide

[1408]

[1409] TLC: Rf 0.32 (hexane:ethyl acetate=2:1);

[1410] NMR (CDCl₃): δ 7.37-6.92 (m, 11H), 4.73-4.29 (m, 6H), 3.84 (d,J=6.6 Hz, 2H), 3.32 (dd, J=12.3, 4.5 Hz, 1H), 3.29 (dd, J=12.3, 6.6 Hz,1H), 3.24-3.17 (br, 1H), 2.81 (dd, J=13.5, 6.6 Hz, 1H), 2.44-2.32 (m,2H), 1.99-1.54 (m, 6H), 1.49-1.04 (m, 4H), 0.95-0.86 (m, 8H).

Example 18(4)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-methoxycarbonylthiazolidin-4-ylcarbonylamino)propanamide

[1411]

[1412] TLC: Rf 0.31 (hexane:ethyl acetate=1:1);

[1413] NMR (CDCl₃): δ 7.22 (d, J=8.7 Hz, 2H), 7.10 (d, J=7.8 Hz, 2H),6.85 (d, J=8.7 Hz, 2H), 4.72-4.24 (m, 6H), 3.79 (s, 3H), 3.65 (brs, 3H),3.31 (dd, J=12.0, 4.2 Hz, 1H), 3.26 (dd, J=12.0, 6.9 Hz, 1H), 3.18-3.00(br, 1H), 2.81 (dd, J=13.8, 6.6 Hz, 1H), 2.46-2.32 (m, 2H), 1.78-1.60(m, 5H), 1.48-1.04 (m, 4H), 0.94-0.80 (m, 2H).

Example 18(5)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-(2-methylpropoxycarbonyl)thiazolidin-4-ylcarbonylamino)propanamide

[1414]

[1415] TLC: Rf 0.17 (hexane:ethyl acetate=2:1);

[1416] NMR (CDCl₃): δ 7.21 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.1 Hz, 2H),6.84 (d, J=8.4 Hz, 2H), 4.72-4.21 (m, 6H), 3.78 (s, 5H), 3.31 (dd,J=12.3, 4.2 Hz, 1H), 3.28 (dd, J=12.3, 6.6 Hz, 1H), 3.25-3.17 (br, 1H),2.80 (dd, J=13.8, 6.6 Hz, 1H), 2.45-2.30 (m, 2H), 1.94-1.62 (m, 6H),1.47-1.04 (m, 4H), 0.98-0.80 (br, 8H).

Example 19˜Example 19(1)

[1417] By the same desired procedure as Reference Example 4→Example5→Example 17, using the compound prepared in Example 2(99), thefollowing compounds of the present invention were obtained.

[1418] Also, (−)-3-t-butoxycarbonylthiazolidin-2-ylcarboxylic acid wasused for the preparation of the compound of Example 19.

[1419] (+)-3-t-butoxycarbonylthiazolidin-2-ylcarboxylic acid was usedfor the preparation of the compound of Example 19 (1).

Example 19(2R)-N-(4-dimethylaminobenzyl)-3-cyclohexylmethylthio-2-(thiazolidin-2-ylcarbonylamino)propanamide

[1420]

[1421] (The absolute configuration of * carbon is not determined, butthe above compound is a single optical isomer.)

[1422] [α]_(D)=−77.07 (c 0.99, CHCl₃);

[1423] TLC: Rf 0.46 (ethyl acetate:hexane=2:1)

[1424] NMR (CDCl₃): δ 7.68 (1H, d, J=7.2 Hz), 7.19-7.12 (2H, m),6.73-6.65 (3H, m), 4.98 (1H, s), 4.49-4.39 (1H, m), 4.34 (2H, d, J=5.4Hz), 3.51-3.39 (1H, m), 3.15-2.74 (11H, m) 2.44 (2H, d, J=6.6 Hz),1.88-0.77 (11H, m).

Example 19(1)(2R)-N-(4-dimethylaminobenzyl)-3-cyclohexylmethylthio-2-(thiazolidin-2-ylcarbonylamino)propanamide

[1425]

[1426] (The absolute configuration of * carbon is not determined, butthe above compound-is a single optical isomer.)

[1427] [α]_(D)=+70.27 (c 1.06, CHCl₃);

[1428] TLC: Rf 0.41 (ethyl acetate:hexane=2:1);

[1429] NMR (CDCl₃): δ 7.69 (1H, d, J=7.4 Hz), 7.19-7.12 (2H, m),6.73-6.65 (2H, m), 6.60 (1H, d, J=5.2 Hz), 5.00 (1H, s), 4.49-4.39 (1H,m), 4.34 (2H, d, J=5.4 Hz), 3.49-3.38 (1H, m), 3.09-2.72 (11H, m) 2.51(1H, dd, J=12.4, 6.6 Hz), 2.44 (1H, dd, J=12.4, 7.0 Hz), 1.88-0.77 (11H,m).

Example 20(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(((4R)-3-t-butoxycarbonylthiazolidin-4-ylmethyl)amino)propanamide

[1430]

[1431] N-methyl morpholine (0.18 ml),(4R)-3-t-butoxycarbonyl-4-formylthiazolidine (355 mg) and sodiumcyanoborohydride (206 mg) were added to a suspention of the compound(611 mg) (obtained by the same desired procedure as Reference Example 4using the compound prepared in Example 2(80)) in ethanol (2 ml). Themixture was stirred for 3.5 hours at room temperature. The reactionmixture was concentrated. Saturated aqueous sodium hydrogencarbonate wasadded to the residue. The mixture was extracted with ethyl acetate. Theextract was washed with saturated aqueous sodium chloride, dried overanhydrous sodium sulfate. The organic layer was concentrated and theresidue was purified by silica gel column chromatography (ethylacetate:hexane=2:1→1:1) to give the compound of the present invention(637.5 mg) having the following physical data.

[1432] TLC: Rf 0.30 (ethyl acetate:hexane=1:2);

[1433] NMR (CD₃OD) δ 7.27-7.20 (m, 2H), 6.89-6.83 (m, 2H), 4.54 (d, J=9Hz, 1H), 4.37 (d, J=14 Hz, 1H), 4.33-4.21 (m, 2H), 4.17 (d, J=9 Hz, 1H),3.77 (3H, s), 3.25 (dd, J=8, 5 Hz), 3.14-3.05 (m, 1H), 2.98-2.80 (m,2H), 2.77-2.60 (m, 3H), 2.41 (dd, J=12, 8 Hz, 1H), 2.40 (dd, J=12, 8 Hz,1H), 1.88-1.60 (m, 5H), 1.55-1.35 (m, 10H), 1.35-1.07 (m, 3H), 1.03-0.85(2H, m).

Example 20(1)˜Example 20(7)

[1434] By the same desired procedure as Example 20, using the compound(obtained by the same desired procedure as Reference Example 4, usingthe compound prepared in Example 2(103)) or the compound (obtained bythe same desired procedure as Reference Example 4, using the compoundprepared in Example 2 (80)), the following compounds of the presentinvention were obtained.

Example 20(1)(2R)-N-(4-phenoxybenzyl)-3-cyclohexylmethylthio-2-(((4R)-3-t-butoxycarbonylthiazolidin-4-ylmethyl)amino)propanamide

[1435]

[1436] TLC: Rf 0.60 (methylene chloride:ethyl acetate=9:1),

[1437] NMR (CD₃OD): δ 7.39-7.28 (m, 4H), 7.14-7.04 (m, 1H), 6.99-6.88(m, 4H), 4.54 (d, J=9.0 Hz, 1H), 4.43 (d, J=14.7 Hz, 1H), 4.37-4.21 (m,1H), 4.33 (d, J=14.7 Hz, 1H), 4.15 (d, J=9.0 Hz, 1H), 3.26 (dd, J=7.6,5.4 Hz, 1H), 3.16-2.60 (m, 6H), 2.41 (d, J=6.6 Hz, 2H), 1.45 (s, 9H),1.90-0.80 (m, 11H).

Example 20(2)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((thiophen-2-ylmethyl)amino)propanamide

[1438]

[1439] TLC: Rf 0.19 (hexane:ethyl acetate=4:1);

[1440] NMR (CDCl₃): δ 7.64 (t, J=5.4 Hz, 1H), 7.22-7.18 (m, 3H),6.95-6.84 (m, 4H), 4.39 (dd, J=14.4, 6.0 Hz, 1H), 4.37 (dd, J=14.4, 6.0Hz, 1H), 3.93 (s, 2H), 3.80 (s, 3H), 3.30 (dd, J=9.3, 3.9 Hz, 1H), 3.03(dd, J=13.8, 3.9 Hz, 1H), 2.63 (dd, J=13.8, 9.3 Hz, 1H), 2.31 (dd,J=12.3, 6.9 Hz, 1H), 2.25 (dd, J=12.3, 6.9 Hz, 1H), 1.83-1.32 (m, 6H),1.28-1.04 (m, 3H), 0.95-0.80 (m, 2H).

Example 20(3)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((cyclohexylmethyl)-amino)propanamide

[1441]

[1442] TLC: Rf 0.24 (hexane:ethyl acetate=4:1);

[1443] NMR (CDCl₃): δ 7.67 (t, J=5.5 Hz, 1H), 7.23-7.16 (m, 2H),6.90-6.83 (m, 2H), 4.40 (dd, J=14.4, 6.2 Hz, 1H), 4.35 (dd, J=14.6, 5.8Hz, 1H), 3.80 (s, 3H), 3.17-3.02 (m, 2H), 2.60-2.24 (m, 5H), 1.87-0.70(m, 22H).

Example 20(4)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(((4RS)-3-t-butoxycarbonyl-1,3-perhydrothiazin-4-ylmethyl)amino)propanamide

[1444]

[1445] TLC: Rf 0.17 (ethyl acetate:hexane=1:2);

[1446] NMR (CD₃OD) δ 7.29-7.20 (m, 2H), 6.91-6.81 (m, 2H), 4.71-4.50 (m,1H), 4.41-4.22 (m, 4H), 3.77 (s, 3H), 3.28-3.19 (m, 1H), 3.03-2.75 (m,3H), 2.71-2.35 (m, 5H), 2.00-1.60 (m, 7H), 1.52-1.34 (m, 1 OH),1.33-1.10 (m, 3H), 1.02-0.84 (m, 2H).

Example 20(5)(2R)-N-(4-phenoxybenzyl)-3-cyclohexylmethylthio-2-((thiophen-2-ylmethyl)-amino)propanamide

[1447]

[1448] TLC: Rf 0.41 (hexane:ethyl acetate=2:1);

[1449] NMR (CD₃OD): δ 7.37-7.25 (m, 5H), 7.12-7.05 (m, 1H), 7.00-6.91(m, 6H), 4.42 (d, J=14.6 Hz, 1H), 4.34 (d, J=14.6 Hz, 1H), 3.98 (d,J=14.1 Hz, 1H), 3.86 (d, J=14.1 Hz, 1H), 3.33-3.28 (m, 1H), 2.83 (dd,J=13.4, 6.0 Hz, 1H), 2.68 (dd, J=13.4, 7.4 Hz, 1H), 2.32 (dd, J=12.6,6.9 Hz, 1H), 2.26 (dd, J=12.6, 6.9 Hz, 1H), 1.84-1.59 (m, 5H), 1.47-1.06(m, 4H), 0.99-0.80 (m, 2H).

Example 20(6)(2R)-N-(4-phenoxybenzyl)-3-cyclohexylmethylthio-2-((cyclohexylmethyl)-amino)propanamide

[1450]

[1451] TLC: Rf 0.52 (hexane:ethyl acetate=2:1)

[1452] NMR (CD₃OD) δ 7.38-7.27 (m, 4H), 7.13-7.04 (m, 1H), 6.98-6.89 (m,4H), 4.45 (d, J=14.6 Hz, 1H), 4.30 (d, J=14.6 Hz, 1H), 3.17 (dd, J=7.4,6.2 Hz, 1H), 2.83 (dd, J=13.2, 6.2 Hz, 1H), 2.65 (dd, J=13.2, 7.4 Hz,1H), 2.42-2.23 (m, 0.4H) 1.90-0.70 (m, 22H).

Example 20(7)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(((4R)-3-(3-methylbutyryl)-thiazolidin-4-ylmethyl)amino)propanamide

[1453]

[1454] TLC: Rf 0.33 (hexane:ethyl acetate=1:1);

[1455] NMR (DMSO-d₆) δ 8.06-8.00 (br, 1H), 7.20 (d, J=8.0 Hz, 2H), 6.85(d, J=8.0 Hz, 2H), 4.76-4.68 (br, 1H), 4.53-4.42 (br, 1H), 4.28-4.18 (m,3H), 3.74 (s, 3H), 3.24-3.21 (m, 1H), 3.09-2.95 (m, 2H), 2.77-2.60.(m,4H), 2.45-2.38.(m, 2H), 2.28-2.17 (m, 3H), 2.09-2.00 (m, 1H), 1.79-1.73(m, 2H), 1.69-1.58 (m, 3H), 1.46-1.38 (m, 1H), 1.26-1.10 (m, 3H),0.99-0.91 (m, 8H).

Example 21˜Example 21 (2)

[1456] By the same desired procedure as Example 17, using the compoundsprepared in Example 20 Example 20(1) and Example 20(4), the followingcompounds of the present invention were obtained.

Example 21(2R)-N-(4-methoxybenzyl)-3-cycloyhexylmethylthio-2-(((4R)-thiazolidin-4-ylmethyl)amino)propanamide

[1457]

[1458] TLC: Rf 0.34 (methylene chloride:methanol=19:1);

[1459] NMR (CDCl₃): δ 7.76-7.66 (m, 1H), 7.23-7.16 (m, 2H), 6.89-6.83(m, 2H), 4.37 (d, J=6 Hz, 2H), 4.16 (d, J=10 Hz, 1H), 4.10 (d, J=10 Hz,1H), 3.80 (3H, s), 3.39 (quintet, J=7 Hz, 1H), 3.19 (dd, J=10, 3 Hz,1H), 3.08 (dd, J=14, 3 Hz, 1H), 2.96 (dd, J=10, 7 Hz, 1H), 2.68 (d, J=7Hz, 2H), 2.61 (dd, J. 14,10 Hz, 1H), 2.47(dd, J=10, 7 Hz, 1H), 2.42 (dd,J=13, 7 Hz, 1H), 2.39(dd, J=13, 7 Hz, 1H), 2.00-1.58 (m, 7H), 1.53-1.36(m, 1H), 1.32-1.05 (m, 3H), 1.02-0.83 (2H, m).

Example 21 (1)(2R)-N-(4-phenoxybenzyl)-3-cyclohexylmethylthio-2-(((4R)-thiazolidin-4-ylmethyl)amino)propanamide

[1460]

[1461] TLC: Rf 0.47 (chloroform:methanol=19:1);

[1462] NMR (CD₃OD): δ 7.40-7.29 (m, 4H), 7.15-7.04 (m, 1H), 7.00-6.90(m, 4H), 4.43 (d, J=14.6 Hz, 1H), 4.34 (d, J=14.6 Hz, 1H), 4.13 (d,J=9.2 Hz, 1H), 4.02 (d, J=9.2 Hz, 1H), 3.78-3.54 (m, 1H), 3.33-3.23 (m,1H), 2.99-2.60 (m, 6H), 2.52 (dd, J=9.8, 7.0 Hz, 1H), 2.41 (d, J=6.6 Hz,2H), 1.90-0.80 (m, 11H).

Example 21 (2)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(((4RS)-1,3-perhydrothiazin-4-ylmethyl)amino)propanamide

[1463]

[1464] TLC: Rf 0.37 (methylene chloride:methanol=9:1);

[1465] NMR (CD₃OD) δ 7.28-7.21 (m, 2H), 6.90-6.83 (m, 2H), 4.42-4.25 (m,2H), 4.08-3.97 (m, 1H), 3.95-3.86 (m, 1H), 3.77 (s, 3H), 3.23-3.13 (m,1H), 3.01-2.76 (m, 2H), 2.76-2.56 (m, 3H), 2.56-2.32 (m, 4H), 1.87-1.60(m, 6H), 1.50-1.08 (m, 5H), 1.03-0.84 (m, 2H).

Example 22(2R)-N-(4-methoxybenzyl)-3-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylmethylthio)-2-((4R)-3-t-butoxycarbonylthiazolidin+4-ylcarbonylamino)propanamide

[1466]

[1467] By the same desired procedure as Example 6, using the compoundprepared in Example 10(10), the compound of the present invention havingthe following physical data was obtained.

[1468] TLC: Rf 0.50 (ethyl acetate:hexane=1:1);

[1469] NMR (CD₃OD): δ 7.27-7.15 (2H, m), 6.90-6.79 (2H, m), 4.67-4.43(4H, m), 4.33 (1H, d, J=15 Hz), 4.31 (1H, d, J=15 Hz), 3.76 (3H, s),3.43-3.25 (1H, m), 3.14 (1H, dd, J=12, 4 Hz), 3.02-2.70 (2H, m), 2.57(1H, dd, J=12, 8 Hz), 2.55 (1H, dd, J=12, 8 Hz), 2.22-2.10 (2H, m),2.10-1.69 (2H, m), 1.61-1.03 (6H, m), 1.45 (9H, s), 0.68 (1H, ddd, J=12,5, 2 Hz).

Example 23(2R)-N-(4-methoxybenzyl)-3-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-ylmethylthio)-2-((4R)-thiazolidin-4-ylcarbonylamino)propanamide-hydrochloride

[1470]

[1471] By the same desired procedure as Example 9, using the compoundprepared in Example 22, the compound of the present invention having thefollowing physical data was obtained.

[1472] TLC: Rf 0.51 (methylene chloride:methanol=19:1);

[1473] NMR (CD₃OD): δ 7.30-7.18 (2H, m), 6.93-6.83 (2H, m), 4.60-4.46(2H, m), 4.39 (2H, s), 4.36-4.24 (2H, m), 3.78 (3H, s), 3.50 (1H, dd,J=12, 7 Hz), 3.24 (1H, dd, J=12, 7 Hz), 2.94 (1H, dd, J=13, 6 Hz), 2.82(1H, dd, J=13, 8 Hz), 2.59 (1H, dd, J=12, 8 Hz), 2.57 (1H, dd, J=12, 8Hz), 2.22-2.11 (2H, m), 2.10-1.89 (1H, m), 1.89-1.70 (1H, m), 1.62-1.03(6H, m), 0.68 (1H, ddd, J=12, 5, 2 Hz).

FORMULATION EXAMPLE Fomulation Example 1

[1474] The following components were admixed in conventional method andpunched out to obtain 100 tablets each containing 50 mg of activeingredient. (2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-t-5.0 g butoxycarbonylthiazolidin-4-ylcarbonylamino)propanamidecarboxymethylcellulose calcium (disintegrating agent) 0.2 g Magnesiumstearate (Lubricating agent) 0.1 g Microcrystaline cellulose 4.7 g

Formulation Example 2

[1475] The following components were admixed in conventional manner. Thesolution was sterilized in conventional manner, placed 5 ml portionsinto ampoules and freezed-dried to obtain 100 ampouls each containing 20mg of active ingredient.(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3- 2.00 gt-butoxycarbonylthiazolidin-4-ylcarbonylamino)propanamide mannitol 20 gdistilled water 500 ml

1. An N-type calcium channel blocker comprising, as an activeingredient, an amino acid derivative of the formula (I):

[wherein R¹ is 1) C1-15 alkyl, 2) C1-8 alkoxy, 3) phenyl, 4) C3-8cycloalkyl, 5) hetero ring, 6) C1-4 alkyl substituted by phenyl, C3-8cycloalkyl, or hetero ring, 7) C1-4 alkoxy substituted by phenyl, C3-8cycloalkyl, or hetero ring, 8) C2-4 alkenyl substituted by phenyl, C3-8cycloalkyl, or hetero ring (with proviso that, all phenyl, C3-8cycloalkyl and hetero ring in R¹ group may be substituted by 1˜3 ofsubstituent selected from the following (i)˜(xi); (i) C1-4 alkyl, (ii)C1-4 alkoxy, (iii) phenyl, (iv) phenoxy, (v) benzyloxy, (vi) —SR⁵ (inwhich R¹ is hydrogen or C1-4 alkyl.), (vii) C2-5 acyl, (viii) halogen,(ix) C1-4 alkoxycarbonyl, (x) nitro, (xi) —NR⁶R⁷ (in which R⁶ and R⁷each independently, is hydrogen, C1-4 alkyl or C1-4 alkoxycarbonyl, orR⁶ and R⁷ taken together with the nitrogen atom to which they areattached may represent 5˜7 membered saturated hetero ring containinganother one nitrogen atom or one oxygen atom.).); A is bond, —CO— or—SO₂—, R² is hydrogen or C1-4 alkyl optionally substituted by onephenyl; D is C1-4 alkylene or C2-4 alkenylene; E is 1) —COO—, 2) —OCO—,3) —CONR⁸— (in which R¹ is hydrogen or C1-4 alkyl.), 4) —NR⁹CO— (inwhich R⁹ is hydrogen or C1-4 alkyl.), 5) O—, 6) —S—, 7) —SO—, 8) —SO₂—,9) —NR¹⁰— (in which R¹⁰ is hydrogen or C1-4 alkyl.), 10) —CO—, 11)—SO₂NR¹¹— (in which R¹¹ is hydrogen or C1-4 alkyl.), or 12) —NR¹²SO₂—(in which R¹² is hydrogen or C1-4 alkyl.); R¹ is 1) carbocyclic ring, 2)hetero ring, or 3) C1-4 alkyl substituted by carbocyclic ring or heteroring (with proviso that, all carbocyclic ring and hetero ring in R, maybe substituted by 1˜3 of substituent selected from the following(i)˜(xi); (i) C1-4 alkyl, (ii) C1-4 alkoxy, (iii) phenyl, (iv) phenoxy,(v) benzyloxy, (vi) —SR¹³ (in which R¹³ is hydrogen or C1-4 alkyl.),(vii) C2-5 acyl, (viii) halogen, (ix) C1-4 alkoxycarbonyl, (x) nitro,(xi) —NR¹⁴R¹⁵ (in which R¹⁴ and R¹⁵ each independently, is hydrogen,C1-4 alkyl or C1-4 alkoxycarbonyl, or R¹⁴ and R¹⁵ taken together withthe nitrogen atom to which they are attached may represent 5˜7 memberedsaturated hetero ring containing another one nitrogen atom or one oxygenatom.).); J is —O— or —NR¹⁶— (in which R¹⁶ is hydrogen or C1-4 alkyl.);R¹ is 1) C1-8 alkyl, 2) carbocyclic ring, 3) hetero ring, 4) C1-8 alkylsubstituted by 1˜3 of substituent selected from the following (i)˜(v);(i) carbocyclic ring, (ii) hetero ring, (iii) COOR¹⁷ (in which R¹⁷ ishydrogen or C1-4 alkyl substituted by one phenyl (in which phenyl may besubstituted by C1-4 alkoxy.), (iv) SR¹³ (in which R¹⁸ is hydrogen orC1-4 alkyl.), (v) OR¹⁹ (in which R¹⁹ is hydrogen or C1-4 alkyl.), orwhen J represents —NR¹⁶— group, R⁴ and R¹⁶ taken together with thenitrogen atom to which they are attached may represent hetero ring (withproviso that, all carbocyclic ring and hetero ring, and hetero ringrepresented by R⁴ and R¹” taken together with the nitrogen atom to whichthey are attached may be substituted by 1˜3 of substituent selected fromthe following (i)˜(xi); (i) C1-4 alkyl, (ii) C1-4 alkoxy, (iii) phenyl,(iv) phenoxy, (v) benzyloxy, (vi) —SR²⁰ (in which R²⁰ is hydrogen orC1-4 alkyl.), (vii) C2-5 acyl, (viii) halogen, (ix) C1-4 alkoxycarbonyl,(x) nitro, (xi) —NR²¹R²² (in which R²¹ and R²² each independently, ishydrogen, C1-4 alkyl or C1-4 alkoxycarbonyl, or R²¹ and R²² takentogether with the nitrogen atom to which they are attached may represent5˜7 hmembered saturated hetero ring containing another one nitrogen atomor one oxygen atom.).).], a non-toxic salt thereof, or a hydratethereof.
 2. A pharmaceutical composition comprising a compound depictedin claim 1 as an active ingredient for the prevention and/or treatmentof cerebral infarct, transient ischemic attack, encephalomyelopathyafter cardiac operation, spinal angiopathy, hypertension with stress,neurosis or epilepsy.
 3. A pharmaceutical composition comprising acompound depicted in claim 1 as an active ingredient for the treatmentof pain.
 4. An amino acid derivative of the formula (I):

[wherein R¹ is 1) C1-15 alkyl, 2) C1-8 alkoxy, 3) phenyl, 4) C3-8cycloalkyl, 5) hetero ring, 6) C1-4 alkyl substituted by phenyl, C3-8cycloalkyl, or hetero ring, 7) C1-4 alkoxy substituted by phenyl, C3-8cycloalkyl, or hetero ring, or 8) C2-4 alkenyl substituted by phenyl,C3-8 cycloalkyl, or hetero ring (with proviso that, all phenyl, C3-8cycloalkyl and hetero in R¹ group may be substituted by 1˜3 ofsubstituent selected from the following (i)˜(xi); (i) C1-4 alkyl, (ii)C1-4 alkoxy, (iii) phenyl, (iv) phenoxy, (v) benzyloxy, (vi) —SR⁵ (inwhich R¹ is hydrogen or C1-4 alkyl.), (vii) C2-5 acyl, (viii) halogen,(ix) C1-4 alkoxycarbonyl, (x) nitro, (xi) —NR⁶R⁷ (in which R⁶ and R⁷each independently, is hydrogen, C1-4 alkyl or C1-4 alkoxycarbonyl, orR⁶ and R⁷ taken together with the nitrogen atom to which they areattached may represent 5˜7 membered saturated hetero ring containinganother one nitrogen atom or one oxygen atom.).); A is bond, —CO— or—SO₂—, R² is hydrogen or C1-4 alkyl optionally substituted by onephenyl; D is C1-4 alkylene or C2-4 alkenylene; E is 1) —COO—, 2) —OCO—,3) —CONR⁸— (in which R¹ is hydrogen or C1-4 alkyl.), 4) —NR⁹CO— (inwhich R⁹ is hydrogen or C1-4 alkyl.), 5) —O—, 6) —S—, 7) —SO—, 8) —SO₂—,9) —NR¹⁰— (in which R¹⁰ is hydrogen or C1-4 alkyl.), 10) —CO—, 11)—SO₂NR¹¹— (in which R¹¹ is hydrogen or C1-4 alkyl.), or 12) —NR¹²SO₂—(in which R¹² is hydrogen or C1-4 alkyl.); R³ is 1) carbocyclic ring, 2)hetero ring, or 3) C1-4 alkyl substituted by carbocyclic ring or heteroring (with proviso that, all carbocyclic ring and hetero ring in R, maybe substituted by 1˜3 of substituent selected from the following(i)˜(xi); (i) C1-4alkyl, (ii) C1-4 alkoxy, (iii) phenyl, (iv) phenoxy,(v) benzyloxy, (vi) —SR¹³ (in which R¹³ is hydrogen or C1-4 alkyl.),(vii) C2-5 acyl, (viii) halogen, (ix) C1-4 alkoxycarbonyl, (x) nitro,(xi) —NR¹⁴R¹⁵ (in which R¹⁴ and R¹⁵ each independently, is hydrogen,C1-4 alkyl or C1-4 alkoxycarbonyl, or R¹⁴ and R¹⁵ taken together withthe nitrogen atom to which they are attached may represent 5˜7 memberedsaturated hetero ring containing another one nitrogen atom or one oxygenatom.).); J is —O— or —NR¹⁶— (in which R¹⁶ is hydrogen or C1-4 alkyl.);R¹ is 1) C1-8 alkyl, 2) carbocyclic ring, 3) hetero ring, 4) C1-8 alkylsubstituted by 1˜3 of substituent selected from the following (i)˜(v);(i) carbocyclic ring, (ii) hetero ring, (iii) COOR¹⁷ (in which R¹⁷ ishydrogen or C1-4 alkyl substituted by one phenyl (in which phenyl may besubstituted by C1-4 alkoxy.), (iv) SR¹⁸ (in which R¹⁸ is hydrogen orC1-4 alkyl.), (v) OR¹⁹ (in which R¹⁹ is hydrogen or C1-4 alkyl.), orwhen J represents —NR¹⁶— group, R⁴ and R¹⁶ taken together with thenitrogen atom to which they are attached may represent hetero ring (withproviso that, all carbocyclic ring and hetero ring, and hetero ringrepresented by R⁴ and R¹⁶ taken together with the nitrogen atom to whichthey are attached may be substituted by 1˜3 of substituent selected fromthe following (i)˜(xi); (i) C1-4 alkyl, (ii) C1-4 alkoxy, (iii) phenyl,(iv) phenoxy, (v) benzyloxy, (vi) —SR²⁰ (in which R²⁰ is hydrogen orC1-4 alkyl.), (vii) C2-5 acyl, (viii) halogen, (ix) C1-4 alkoxycarbonyl,(x) nitro, (xi) —NR²¹R²² (in which R²¹ and R²² each independently, ishydrogen, C1-4 alkyl or C1-4 alkoxycarbonyl, or R²¹ and R²² takentogether with the nitrogen atom to which they are attached may represent5˜7 membered saturated hetero ring containing another one nitrogen atomor one oxygen atom.).). With proviso that, the following compounds(1)-(37) are excluded: (1)N-(2-amino-5-nitrophenyl)-3-benzyloxy-2-t-butoxycarbonylaminopropanamide,(2) N-phenyl-3-benzyloxy-2-t-butoxycarbonylaminopropanamide, (3)N-(2-aminophenyl)-3-benzyloxy-2-t-butoxycarbonylaminopropanamide, (4)N-(4-nitrophenyl)-3-benzyloxy-2-t-butoxycarbonylaminopropanamide, (5)N-(adamantan-2-yl)-3-benzyloxy-2-t-butoxycarbonylaminopropanamide, (6)N-(pyridin-4-yl)-3-benzyloxy-2-t-butoxycarbonylaminopropanamide, (7)N-(2-aminophenyl)-3-benzyloxy-2-t-butoxycarbonylaminobutanamide, (8)N-(4-nitrophenyl)-3-benzyloxy-2-t-butoxycarbonylaminobutanamide, (9)N-(3-bromo-4,5-dihydroisoxazol-5-ylmethyl)-3-benzyloxy-2-t-butoxycarbonylaminobutanamide,(10)N-methyl-N-(2,6-dimethoxy-4-methylphenyl)-3-benzyloxy-2-tbutoxycarbonylaminopropanamide,(11) N-(4-nitrophenyl)-3-benzylthio-2-t-butoxycarbonylaminopropanamide,(12) N-(quinolin-6-yl)-3-benzylthio-2-t-butoxycarbonylaminopropanamide,(13) N-(2-aminophenyl)-3-benzylthio-2-t-butoxycarbonylaminopropanamide,(14)N-(adamantan-2-yl)-3-(3-ethoxycarbonylpyridin-2-ylthio)-2-tbutoxycarbonylaminopropanamide,(15)N-methyl-N-(2-ethoxyphenyl)-3-(3-methoxycarbonylpyridin-2-yl)-2-tbutoxycarbonylaminopropanamide,(16)N-(4-methoxycarbonylphenyl)-3-benzylthio-2-benzyloxycarbonylaminopropanamide,(17)N-(3-bromo-4,5-dihydroisoxazol-5-ylmethyl)-3-benzylthio-2-benzyloxycarbonylaminopropanamide,(18)N-(2-methylphenyl)-3-benzylthio-2-benzyloxycarbonylaminopropanamide,(19)N-(3-methylphenyl)-3-benzylthio-2-benzyloxycarbonylaminopropanamide,(20)N-(4-methylphenyl)-3-benzylthio-2-benzyloxycarbonylaminopropanamide,(21) N-phenyl-3-benzylthio-2-benzyloxycarbonylaminopropanamide, (22)N-(naphthalen-2-yl)-3-benzylthio-2-benzyloxycarbonylaminopropanamide,(23)N-(naphthalen-1-yl)-3-benzylthio-2-benzyloxycarbonylaminopropanamide,(24) N-benzyl-3-benzylthio-2-benzyloxycarbonylaminopropanamide, (25)N-(4-chlorophenyl)-3-benzylthio-2-benzyloxycarbonylaminopropanamide,(26) N-(4-bromophenyl)-3-benzylthio-2-benzyloxycarbonylaminopropanamide,(27) N-(4-nitrophenyl)-3-benzylthio-2-benzyloxycarbonylaminopropanamide,(28)N-(1,2,3,4-tetrahydronaphthalen-2yl)-3-benzylthio-2-(4-chlorobenzyloxycarbonylamino)propanamide,(29)N-methyl-N-(2-ethoxyphenyl)-3-(3-methoxycarbonylpyridin-2-ylthio)-2-(3,4-dichlorophenylcarbonylamino)propanamide,(30) 3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid4-nitrobenzyl ester, (31)3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid.benzylester, (32) 3-cycloheptyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.benzyl ester, (33)3-cyclooctyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid.benzylester, (34)3-(2-isopropyl-5-methylcyclohexyloxycarbonyl)-2-t-butoxycarbonylaminopropanoicacid.benzyl ester, (35)N-(benzyloxycarbonylmethyl)-3-(2-isopropyl-5-methylcyclohexyloxycarbonyl)-2-t-butoxycarbonylaminopropanamide,(36) 3-cyclohexyloxycarbonyl-2-benzyloxycarbonylaminopropanoicacid.benzyl ester, and (37) N-phenyl-2,3-bis(benzoylamino)propanamide.],a non-toxic salt thereof, or a hydrate thereof.
 5. A compound accordingto claim 4, wherein E is —S—, —SO—, or —SO₂—.
 6. A compound according toclaim 4, wherein E is —O—.
 7. A compound according to claim 4, wherein Eis —COO—.
 8. A compound according to claim 4, wherein E is —OCO—,—CONR⁸—, —NR⁹CO—, —NR¹⁰—, —CO—, —SO₂NR¹¹—, or NR¹²SO₂— (in which R⁸, R⁹,R¹⁰, R¹¹ and R¹² are the same meanings as described in claim 4.).
 9. Acompound according to claim 5, which is (1)(2R)-3-(4-methoxybenzylthio)-2-t-butoxycarbonylaminopropanoicacid.cyclohexyl ester, (2)(2R)-N-(4-methoxybenzyl)-3-(4-methoxybenzylthio)-2-t-butoxycarbonylaminopropanamide,(3)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-t-butoxycarbonylaminopropanamide,(4)(2S)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-t-butoxycarbonylaminopropanamide,(5)(2R)-N-(4-methoxybenzyl)-3-cyclopentylmethylthio-2-t-butoxycarbonylaminopropanamide,(6)(2S)-N-(4-methoxybenzyl)-3-cyclopentylmethylthio-2-t-butoxycarbonylaminopropanamide,(7)(2R)-N-(4-nitrobenzyl)-3-cyclohexylmethylthio-2-t-butoxycarbonylaminopropanamide,(8)(2R)-N-(furan-2-ylmethyl)-3-cyclohexylmethylthio-2-t-butoxycarbonylaminopropanamide,(9)(2R)-N-(4-dimethylaminobenzyl)-3-cyclohexylmethylthio-2-t-butoxycarbonylaminopropanamide,(10) (2R)-2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanoicacid.4-methoxybenzyl ester, (11)(2R)-N-(4-methoxycyclohexylmethyl)-2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide,(12)(2R)-N-(4-methoxycyclohexylmethyl)-2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide,(13)(2R)-N-(4-phenoxybenzyl)-2-t-butoxycarbonylamino-3-cyclohexylmethyl-thiopropanamide,(14)(2R)-N-((1S)-1-(4-nitrophenyl)ethyl)-2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide,(15)(2R)-N-((1R)-1-(4-nitrophenyl)ethyl)-2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide,(16)(2R)-N-methyl-N-(4-nitrobenzyl)-2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide,(17)(2R)-N-(1-(4-methoxyphenyl)-1-methylethyl)-2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide,(18)(2R)-N-(1-methyl-1-(4-nitrophenyl)ethyl)-2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide,(19)(2S)-N-((1R)-1-(4-nitrophenyl)ethyl)-2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide,(20)(2R)-N-methyl-N-(4-methoxybenzyl)-2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide,(21)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(N′-methyl-N′-(t-butoxycarbonyl)amino)propanamide,(22)(2R)-N-(4-benzyloxybenzyl)-2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide,(23)(2R)-N-(3-benzyloxy-4-methoxybenzyl)-2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide,(24)N-((1R)-2-cyclohexylmethylthio-1-(4-phenylpiperazin-1-ylcarbonyl)ethyl)carbamideacid.t-butyl ester, (25)(2R)-N-(2-phenoxypyridin-5-yl)-2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide,(26)(2R)-N-(2-phenoxypyridin-5-ylmethyl)-2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide,(27)(2R)-N-(4-(morpholin-4-yl)benzyl)-2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide,(28)(2R)-N-(1-phenylpiperidin-4-yl)-2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide,(29)(2R)-N-(1-methylpiperidin-4-yl)-2-t-butoxycarbonylamino-3-cyclohexylmethylthiopropanamide,(30)(2R)-N-(4-methoxybenzyl)3-cyclohexylmethylthio-2-cyclopentylcarbonylaminopropanamide,(31)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-cyclohexylcarbonylaminopropanamide,(32)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-cyclobutylcarbonylaminopropanamide,(33)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-cycloheptylcarbonylaminopropanamide,(34)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(4-methoxycyclohexylcarbonylamino)propanamide,(35)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((2RS)-3-t-butoxycarbonylthiazolidin-2-ylcarbonylamino)propanamide,(36)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(2-methylpropylcarbonylamino)propanamide,(37)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(2-methylpropyloxycarbonylamino)propanamide,(38)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(1-(t-butoxycarbonyl)piperidin-4-ylcarbonylamino)propanamide,(39)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(4-(t-butoxycarbonylamino)cyclohexylcarbonylamino)propanamide,(40)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(tetrahydrofuran-2-ylcarbonylamino)propanamide,(41)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino)propanamide,(42)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((2S)-1-t-butoxycarbonylpyrrolidin-2-ylcarbonylamino)propanamide,(43)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(thiazol-4-ylcarbonylamino)propanamide,(44)(2R)-N-((1R)-1-(4-nitrophenyl)ethyl)-3-cyclohexylmethylthio-2-((4R)-3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino)propanamide,(45)(2S)-N-((1R)-1-(4-nitrophenyl)ethyl)-3-cyclohexylmethylthio-2-((4R)-3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino)propanamide, (46)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(2-t-butoxycarbonylaminothiazol-4-ylcarbonylamino)propanamide, (47)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((4S)-3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino)propanamide, (48)(2R)-N-(4-nitrobenzyl)-3-cyclohexylmethylthio-2-((4R)-3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino)propanamide, (49)(2R)-N-(4-nitrobenzyl)-3-cyclohexylmethylthio-2-((2RS)-3-t-butoxycarbonylthiazolidin-2-ylcarbonylamino)propanamide, (50)(2R)-N-(4-nitrobenzyl)-3-cyclohexylmethylthio-2-((4R)-3-methylthiazolidin-4-ylcarbonylamino)propanamide,(51)(2R)-N-(4-dimethylaminobenzyl)-3-cyclohexylmethylthio-2-((4R)-3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino)propanamide, (52)(2R)-N-(4-dimethylaminobenzyl)-3-cyclohexylmethylthio-2-((2RS)-3-t-butoxycarbonylthiazolidin-2-ylcarbonylamino)propanamide, (53)(2R)-N-(4-nitrobenzyl)-3-cyclohexylmethylthio-2-(1-t-butoxycarbonylimidazol-4-ylcarbonylamino)propanamide, (54)(2R)-N-(4-nitrobenzyl)-3-cyclohexylmethylthio-2-((4R)-2,2-dimethylthiazolidin-4-ylcarbonylamino)propanamide,(55)(2R)-N-(4-nitrobenzyl)-3-cyclohexylmethylthio-2-(thiophen-2-ylcarbonylamino)propanamide,(56)(2R)-N-(4-nitrobenzyl)-3-cyclohexylmethylthio-2-(5-methyloxazol-2-ylcarbonylamino)propanamide,(57)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(3-t-butoxycarbonylthiazolidin-2-ylcarbonylamino)propanamide,(58)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(3-t-butoxycarbonylthiazolidin-2-ylcarbonylamino)propanamide,(59)(2R)-N-(4-dimethylaminobenzyl)-3-cyclohexylmethylthio-2-cyclohexylcarbonylaminopropanamide,(60)(2S)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(3-t-butoxycarbonylthiazolidin-2-ylcarbonylamino)propanamide,(61)(2S)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((4S)₃-t-butoxycarbonylthiazolidin-4-ylcarbonylamino)propanamide, (62)(2S)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-t-butoxycarbonylthiazolidin4-ylcarbonylamino) propanamide, (63)(2R)-N-methyl-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-tbutoxycarbonylthiazolidin-4-ylcarbonylamino)propanamide, (64)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-N′-methyl-N′-(3-t-butoxycarbonylthiazolidin-4-ylcarbonyl)amino)propanamide,(65)(2R)-N-(4-phenoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino)propanamide, (66)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((2RS,4R)-3-t-butoxycarbonyl-2-(2-methylpropyl)thiazolidin-4-ylcarbonylamino)propanamide, (67)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(pyridin-3-ylcarbonylamino)propanamide,(68)(2R)-N-(4-benzyloxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino)propanamide, (69)(2R)-N-(3-benzyloxy-4-methoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino)propanamide,(70)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(pyridin-4-ylcarbonylamino)propanamide,(71) (2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((2RS,4R)-3-t-butoxycarbonyl-2-phenylthiazolidin-4-ylcarbonylamino)propanamide,(72)(4R)-N-((1R)-2-cyclohexylmethylthio-1-(4-phenylpiperazin-1-ylcarbonyl)ethyl)-3-t-butoxycarbonylthiazolidin-4-ylcarboxamide,(73)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((3RS)-4-t-butoxycarbonylthiomorpholin-3-ylcarbonylamino)propanamide, (74)(2R)-N-(4-phenoxybenzyl)-3-cyclohexylmethylthio-2-((3RS)-4-t-butoxycarbonylthiomorpholin-3-ylcarbonylamino)propanamide, (75)(2R)-N-(2-phenoxypyridin-5-yl)-3-cyclohexylmethylthio-2-((4R)-3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino)propanamide, (76)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((2RS)-4-t-butoxycarbonylthiomorpholin-2-ylcarbonylamino)propanamide, (77)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((4RS)-3-t-butoxycarbonyl-1,3-perhydrothiazin-4-ylcarbonylamino)propanamide, (78)(2R)-N-(2-phenoxypyridin-5-ylmethyl)-3-cyclohexylmethylthio-2-((4R)-3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino)propanamide, (79)(2R)-N-(4-(morpholin-4-yl)benzyl)-3-cyclohexylmethylthio-2-((4R)-3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino)propanamide, (80)(2R)-N-(4-phenoxybenzyl)-3-cyclohexylmethylthio-2-((4RS)-3-t-butoxycarbonyl-1,3-perhydrothiazin-4-ylcarbonylamino)propanamide, (81)(2R)-N-(1-phenylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino)propanamide, (82)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-2-oxothiazolidin-4-ylcarbonylamino)propanamide,(83)(2R)-N-(1-methylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino)propanamide,(84)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylsulfonyl-2-t-butoxycarbonyl-aminopropanamide,(85)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylsulfinyl-2-t-butoxycarbonylaminopropanamide,(86)(2R)-N-(4-methoxybenzyl)-3-cyclopentylmethylsulfonyl-2-t-butoxycarbonylaminopropanamide,(87)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylsulfonyl-2-cyclohexylcarbonylaminopropanamide,(88)(2S)-N-(4-methoxybenzyl)-3-cyclopentylmethylsulfonyl-2-t-butoxycarbonylaminopropanamide,(89)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylsulfonyi-2-(4-methoxycyclohexylcarbonylamino)propanamide,(90)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylsulfonyl-2-(4-methoxycyclohexylcarbonylamino)propanamide,(91)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylsulfonyl-2-cyclobutylcarbonylaminopropanamide,(92)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylsulfonyl-2-(tetrahydrofuran-2-ylcarbonylamino)propanamide,(93)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylsulfonyl-2-cycloheptylcarbonylaminopropanamide,(94)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylsulfonyl-2-(tetrahydrofuran-3-ylcarbonylamino)propanamide, (95)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylsulfonyl-2-((2RS)-3-t-butoxycarbonylthiazolidin-2-ylcarbonylamino)propanamide, (96)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylsulfonyl-2-((4R)-3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino)propanamide, (97)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylsulfonyl-2-(3-t-butoxycarbonylthiazolidin-2-ylcarbonylamino)propanamide, (98)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylsulfinyl-2-((4R)-3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino)propanamide, (99)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylsulfonyl-2-(1-t-butoxycarbonylpiperidin-4-ylcarbonylamino)propanamide, (100)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylsulfonyl-2-(4-t-butoxycarbonylaminocyclohexylcarbonylamino)propanamide,(101)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylsulfonyl-2-((2RS)-thiazolidin-2-ylcarbonylamino)propanamide, (102)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(piperidin-4-ylcarbonylamino)propanamide,(103)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(4-aminocyclohexylcarbonylamino)propanamide,(104)(2R)-N-((1R)-1-(4-nitrophenyl)ethyl)-3-cyclohexylmethylthio-2-((4R)-thiazolidin-4-ylcarbonylamino)propanamide, (105)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((4S)-thiazolidin-4-ylcarbonylamino)propanamide,(106)(2R)-N-(4-nitrobenzyl)-3-cyclohexylmethylthio-2-((4R)-thiazolidin-4-ylcarbonylamino)propanamide,(107)(2R)-N-(4-nitrobenzyl)-3-cyclohexylmethylthio-2-((2RS)-thiazolidin-2-ylcarbonylamino)propanamide,(108)(2R)-N-(4-nitrobenzyl)-3-cyclohexylmethylthio-2-(imidazol-4-ylcarbonylamino)propanamide,(109)(2R)-N-(4-dimethylaminobenzyl)-3-cyclohexylmethylthio-2-((4R)-thiazolidin-4-ylcarbonylamino)propanamide, (110)(2R)-N-(4-dimethylaminobenzyl)-3-cyclohexylmethylthio-2-((2RS)-thiazolidin-2-ylcarbonylamino)propanamide, (111)(2R)-N-(4-benzyloxybenzyl)-3-cyclohexylmethylthio-2-((4R)-thiazolidin-4-ylcarbonylamino)propanamide, (112)(2R)-N-(3-benzyloxy-4-methoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-thiazolidin-4-ylcarbonylamino)propanamide, (113)(2R)-N-(4-methoxybenzyl)-3-(tetrahydropyran-2-yl)methylthio-2-t-butoxycarbonylaminopropanamide,(114)(2R)-N-(4-methoxybenzyl)-3-(bicyclo[2.2.1]heptan-2-ylmethylthio)-2-t-butoxycarbonylaminopropanamide,(115)(2R)-N-(4-methoxybenzyl)-3-(4-methoxycyclohexylmethylthio)-2-t-butoxycarbonylaminopropanamide,(116)(2R)-N-(4-methoxybenzyl)-3-(1-methylpiperidin-2-ylmethylthio)-2-t-butoxycarbonylaminopropanamide,(117)(2R)-N-(4-methoxybenzyl)-3-(pyridin-4-ylmethylthio)-2-t-butoxycarbonylaminopropanamide,(118)(2R)-N-(4-methoxybenzyl)-3-(quinolin-2-ylmethylthio)-2-t-butoxycarbonylaminopropanamide,(119)(2R)-N-(4-methoxybenzyl)-3-(imidazol-4-ylmethylthio)-2-t-butoxycarbonylaminopropanamide,(120) (2R)-N-(4-methoxybenzyl)-3-((1R, 4R,5R)-bicyclo[2.2.1]hept-2-en-5-ylmethylthio)-2-t-butoxycarbonylaminopropanamide,(121) (2R)-N-(4-methoxybenzyl)-3-((1S, 4S,5S)-bicyclo[2.2.1]hept-2-en-5-ylmethylthio)-2-t-butoxycarbonylaminopropanamide,(122) (2R)-N-(4-methoxybenzyl)-3-((1S, 2R,4R)-bicyclo[2.2.1]heptan-2-ylmethylthio)-2-t-butoxycarbonylaminopropanamide,(123) (2R)-N-(4-methoxybenzyl)-3-((1R, 2S,4S)-bicyclo[2.2.1]heptan-2-ylmethylthio)-2-t-butoxycarbonylaminopropanamide,(124)(2R)-N-(4-methoxybenzyl)-3-(piperidin-1-ylsulfonyl)-2-t-butoxycarbonylaminopropanamide,(125)(2R)-N-(4-phenoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-thiazolidin-4-ylcarbonylamino)propanamide,(126)(2R)-N-(1-phenylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-thiazolidin-4-ylcarbonylamino)propanamide,(127)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((2RS)-thiazolidin-2-ylcarbonylamino)propanamide, (128)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-thiazolidin-4-ylcarbonylamino)propanamide,(129)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(2-aminothiazol-4-ylcarbonylamino)propanamide,(130)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(thiazolidin-2-ylcarbonylamino)propanamide,(131) (2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((2RS,4R)-2-(2-methylpropyl)thiazolidin-4-ylcarbonylamino)propanamide, (132)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((2RS,4R)-2-phenylthiazolidin-4-ylcarbonylamino)propanamide, (133)(4R)-N-((1R)-2-cyclohexylmethylthio-1-(4-phenylpiperazin-1-ylcarbonyl)ethyl)thiazolidin-4-ylcarboxamide,(134)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((3RS)-thiomorpholin-3-ylcarbonylamino)propanamide, (135)(2R)-N-(4-phenoxybenzyl)-3-cyclohexylmethylthio-2-((3RS)-thiomorpholin-3-ylcarbonylamino)propanamide, (136)(2R)-N-(2-phenoxypyridin-5-yl)-3-cyclohexylmethylthio-2-((4R)-thiazolidin-4-ylcarbonylamino)propanamide,(137)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((2RS)-thiomorpholin-2-ylcarbonylamino)propanamide, (138)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((4RS)-1,3-perhydrothiazin-4-ylcarbonylamino)propanamide,(139)(2R)-N-(2-phenoxypyridin-5-ylmethyl)-3-cyclohexylmethylthio-2-((4R)-thiazolidin-4-ylcarbonylamino)propanamide, (140)(2R)-N-(4-(morpholin-4-yl)benzyl)-3-cyclohexylmethylthio-2-((4R)-thiazolidin-4-ylcarbonylamino)propanamide, (141)(2R)-N-(4-phenoxybenzyl)-3-cyclohexylmethylthio-2-((4RS)-1,3-perhydrothiazin-4-ylcarbonylamino)propanamide,(142)(2R)-N-(1-methylpiperidin-4-yl)-3-cyclohexylmethylthio-2-((4R)-thiazolidin-4-ylcarbonylamino)propanamide, (143)(2R)-N-((1R)-1-(4-nitrophenyl)ethyl)-3-cyclohexylmethylthio-2-((4R)-3-(2-methylpropylcarbonyl)thiazolidin-4-ylcarbonylamino)propanamide,(144)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((2RS)-3-acetylthiazolidin-2-ylcarbonylamino)propanamide,(145)(2R)-N-(4-phenoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-methoxycarbonylthiazolidin-4-ylcarbonylamino)propanamide,(146)(2R)-N-(4-phenoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-(2-methylpropoxycarbonyl)thiazolidin-4-ylcarbonylamino)propanamide,(147)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-methoxycarbonylthiazolidin-4-ylcarbonylamino)propanamide,(148)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((4R)-3-(2-methylpropoxycarbonyl)thiazolidin-4-ylcarbonylamino)propanamide,(149)(2R)-N-(4-dimethylaminobenzyl)-3-cyclohexylmethylthio-2-(thiazolidin-2-ylcarbonylamino)propanamide,(150)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(((4R)-3-t-butoxycarbonylthiazolidin-4-ylmethyl)amino)propanamide,(151)(2R)-N-(4-phenoxybenzyl)-3-cyclohexylmethylthio-2-(((4R)-3-t-butoxycarbonylthiazolidin-4-ylmethyl)amino)propanamide,(152)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((thiophen-2-ylmethyl)amino)propanamide,(153)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-((cyclohexylmethyl)amino)propanamide,(154)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(((4RS)-3-t-butoxycarbonyl-1,3-perhydrothiazin-4-ylmethyl)amino)propanamide, (155)(2R)-N-(4-phenoxybenzyl)-3-cyclohexylmethylthio-2-((thiophen-2-ylmethyl)amino)propanamide,(156)(2R)-N-(4-phenoxybenzyl)-3-cyclohexylmethylthio-2-((cyclohexylmethyl)amino)propanamide,(157)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(((4R)-3-(3-methylbutyryl)thiazolidin-4-ylmethyl)amino)propanamide,(158)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(((4R)-thiazolidin-4-ylmethyl)amino)propanamide,(159)(2R)-N-(4-phenoxybenzyl)-3-cyclohexylmethylthio-2-(((4R)-thiazolidin-4-ylmethyl)amino)propanamide, (160)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethylthio-2-(((4RS)-1,3-perhydrothiazin-4-ylmethyl)amino)propanamide,(161) (2R)-N-(4-methoxybenzyl)-3-((1S, 2R,4R)-bicyclo[2.2.1]heptan-2-ylmethylthio)-2-((4R)-3-t-butoxycarbonylthiazolidin-4-ylcarbonylamino)propanamide,or (162) (2R)-N-(4-methoxybenzyl)-3-((1S, 2R,4R)-bicyclo[2.2.1]heptan-2-ylmethylthio)-2-((4R)-thiazolidin-4-ylcarbonylamino)propanamide,or a non-toxic salt thereof, or a hydrate thereof.
 10. A compoundaccording to claim 6, which is (1)(2S)-N-(4-methoxybenzyl)-3-cyclohexylmethoxy-2-t-butoxycarbonylaminopropanamide,(2) (2R)-3-cyclohexylmethoxy-2-t-butoxycarbonylaminopropanoicacid.4-methoxybenzyl ester, (3)(2S)-3-cyclohexylmethoxy-2-t-butoxycarbonylaminopropanoicacid.4-methoxybenzyl ester, (4)(2S)-N-(4-methoxybenzyl)-3-benzyloxy-2-t-butoxycarbonylaminopropanamide,(5)(2S)-N-(4-dimethylaminobenzyl)-3-cyclohexylmethoxy-2-t-butoxycarbonylaminopropanamide,(6)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethoxy-2-t-butoxycarbonylaminopropanamide,(7)(2S)-N-methyl-N-(4-methoxybenzyl)-3-cyclohexylmethoxy-2-t-butoxycarbonylaminopropanamide,(8)(2RS)-N-(4-methoxybenzyl)-4-cyclohexylmethoxy-2-t-butoxycarbonylaminobutanamide,(9)(2S)-N-(4-nitrobenzyl)-3-cyclohexylmethoxy-2-t-butoxycarbonylaminopropanamide,(10)(2S)-N-(4-methoxybenzyl)-3-(2-cyclohexenyloxy)-2-t-butoxycarbonylaminopropanamide,(11)(2S)-N-(4-methoxybenzyl)-3-cyclohexyloxy-2-1-butoxycarbonylaminopropanamide,(12)(2S)-N-(4-methoxybenzyl)-3-cyclopentylmethoxy-2-t-butoxycarbonylaminopropanamide,(13)(2S)-N-(4-methoxybenzyl)-4-(2-cyclohexenyloxy)-2-t-butoxycarbonylaminobutanamide,(14)(2S)-N-(4-methoxybenzyl)-4-cyclohexyloxy-2-t-butoxycarbonylaminobutanamide,(15)(2R)-N-(4-nitrobenzyl)-3-cyclohexylmethoxy-2-t-butoxycarbonylaminopropanamide,(16)(2S)-N-(4-methoxybenzyl)-3-cyclohexylmethoxy-2-benzoylaminopropanamide,(17)(2S)-N-(4-methoxybenzyl)-3-cyclohexylmethoxy-2-phenylsulfonylaminopropanamide,(18)(2S)-N-(4-methoxybenzyl)-3-cyclohexylmethoxy-2-pivaloylaminopropanamide,(19)(2S)-N-(4-methoxybenzyl)-3-cyclohexylmethoxy-2-(4-methoxybenzoylamino)propanamide,(20)(2S)-N-(4-methoxybenzyl)-3-cyclohexylmethoxy-2-(4-nitrobenzoylamino)propanamide,(21)(2S)-N-(4-methoxybenzyl)-3-cyclohexylmethoxy-2-(12-methyltridecylcarbonylamino)propanamide,(22)(2S)-N-(4-methoxybenzyl)-3-cyclohexylmethoxy-2-cyclohexylcarbonylaminopropanamide,(23)(2S)-N-(4-methoxybenzyl)-3-cyclohexylmethoxy-2-(4-methoxyphenylsulfonylamino)propanamide,(24)(2S)-N-(4-methoxybenzyl)-3-cyclohexylmethoxy-2-cyclohexylsulfonylaminopropanamide,or (25)(2R)-N-(4-methoxybenzyl)-3-cyclohexylmethoxy-2-cyclohexylcarbonylaminopropanamide,or a non-toxic salt thereof, or a hydrate thereof.
 11. A compoundaccording to claim 7, which is (1)(2S)-3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.benzyl ester, (2)(2S)-3-benzyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.cyclohexyl ester, (3)(2S)-3-benzyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.cyclopentyl ester, (4)(2R)-3-benzyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.cyclohexyl ester, (5)(2R)-3-benzyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.cyclopentyl ester, (6)(2R)-3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.benzyl ester, (7)(2S)-4-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminobutanoicacid.benzyl ester, (8)(2R)-4-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminobutanoic acid.benzylester, (9) (2R)-4-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminobutanoicacid.benzyl ester, (10)(2S)-4-benzyloxycarbonyl-2-t-butoxycarbonylaminobutanoic acid.cyclohexylester, (11) (2S)-4-benzyloxycarbonyl-2-t-butoxycarbonylaminobutanoicacid.cyclopentyl ester, (12)(2R)-4-benzyloxycarbonyl-2-t-butoxycarbonylaminobutanoic acid.cyclohexylester, (13) (2R)-4-benzyloxycarbonyl-2-t-butoxycarbonylaminobutanoicacid cyclopentyl ester, (14)(2S)-3-cyclopentyloxycarbonyl-2-(N-t-butoxycarbonyl-N-methylamino)propanoicacid.4-nitrobenzyl ester, (15)(2S)-3-cyclohexyloxycarbonyl-2-(N-t-butoxycarbonyl-N-amino)propanoicacid.4-nitrobenzyl ester, (16)(2S)-3-cyclobutyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.benzyl ester, (17)(2S)-3-(adamantan-2-yloxycarbonyl)-2-t-butoxycarbonylaminopropanoicacid.benzyl ester, (18)(2S)-3-(adamantan-1-yloxycarbonyl)-2-t-butoxycarbonylaminopropanoicacid.benzyl ester, (19)(2S)-4-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminobutanoicacid.4-nitrobenzyl ester, (20)(2S)-3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.4-fluorobenzyl ester, (21)(2R)-3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.4-fluorobenzyl ester, (22)(2S)-3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.4-methoxybenzyl ester, (23)(2R)-3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.4-methoxybenzyl ester, (24)(2S)-3-cyclohexyloxycarbonyl-2-benzyloxycarbonylaminopropanoicacid.4-nitrobenzyl ester, (25)(2S)-3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid4-nitrophenethyl ester, (26)(2S)-N-benzyl-3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanamide,(27) (2S)-3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid4-methoxybenzyl ester, (28)(2S)-3-(4-methoxybenzyloxycarbonyl)-2-t-butoxycarbonylaminopropanoicacid.cyclohexyl ester, (29)(2S)-3-(4-nitrobenzyloxycarbonyl)-2-t-butoxycarbonylaminopropanoicacid.cyclohexyl ester, (30)(2S)-3-(4-methoxybenzyloxycarbonyl)-2-t-butoxycarbonylaminopropanoicacid cyclopentyl ester, (31)(2S)-3-(4-nitrobenzyloxycarbonyl)-2-t-butoxycarbonylaminopropanoic acidcyclopentyl ester, (32)(2R)-3-(4-methoxybenzyloxycarbonyl)-2-t-butoxycarbonylaminopropanoicacid.cyclohexyl ester, (33)(2R)-3-(4-nitrobenzyloxycarbonyl)-2-t-butoxycarbonylaminopropanoicacid.cyclohexyl ester, (34)(2R)-3-(4-methoxybenzyloxycarbonyl)-2-t-butoxycarbonylaminopropanoicacid.cyclopentyl ester, (35)(2R)-3-(4-nitrobenzyloxycarbonyl)-2-t-butoxycarbonylaminopropanoic acidcyclopentyl ester, (36)(2R)-3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.4-methoxybenzyl ester, (37)(2S)-4-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminobutanoicacid.4-methoxybenzyl ester, (38)(2S)-4-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminobutanoicacid.4-methoxybenzyl ester, (39)(2S)-4-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminobutanoicacid.4-nitrobenzyl ester, (40)(2R)-4-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminobutanoicacid.4-methoxybenzyl ester, (41)(2R)-4-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminobutanoicacid.4-nitrobenzyl ester, (42)(2R)-4-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminobutanoic acid4-methoxybenzyl ester, (43)(2R)-4-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminobutanoic acid4-nitrobenzyl ester, (44)(2S)-4-(4-methoxybenzyloxycarbonyl)-2-t-butoxycarbonylaminobutanoicacid.cyclohexyl ester, (45)(2S)-4-(4-nitrobenzyloxycarbonyl)-2-t-butoxycarbonylaminobutanoicacid.cyclohexyl ester, (46)(2S)-4-(4-methoxybenzyloxycarbonyl)-2-t-butoxycarbonylaminobutanoicacid.cyclopentyl ester, (47)(2S)-4-(4-nitrobenzyloxycarbonyl)-2-t-butoxycarbonylaminobutanoic acidcyclopentyl ester, (48)(2R)-4-(4-methoxybenzyloxycarbonyl)-2-t-butoxycarbonylaminobutanoicacid.cyclohexyl ester, (49)(2R)-4-(4-nitrobenzyloxycarbonyl)-2-t-butoxycarbonylaminobutanoicacid.cyclohexyl ester, (50)(2R)-4-(4-methoxybenzyloxycarbonyl)-2-t-butoxycarbonylaminobutanoicacid.cyclopentyl ester, (51)(2R)-4-(4-nitrobenzyloxycarbonyl)-2-t-butoxycarbonylaminobutanoicacid.cyclopentyl ester, (52)(2S)-N-(4-methoxybenzyl)-3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanamide,(53)(2S)-N-(4-methoxybenzyl)-3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanamide,(54) (2S)-3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.2-pyridylmethyl ester, (55)(2S)-3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.4-t-butylbenzyl ester, (56)(2S)-3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid2-methoxybenzyl ester, (57)(2S)-3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid3-methoxybenzyl ester, (58)(2S)-3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid3-pyridylmethyl ester, (59)(2S)-3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid4-pyridylmethyl ester, (60)(2S)-3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid4-chlorobenzyl ester, (61)(2S)-3-cyclopentyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid4-bromobenzyl ester, (62)(2S)-3-cyclopentyloxycarbonyl-2-(N-methyl-N-t-butoxycarbonylamino)propanoicacid.4-methoxybenzyl ester, (63)(2S)-3-cyclohexyloxycarbonyl-2-(N-methyl-N-t-butoxycarbonylamino)propanoicacid.4-methoxybenzyl ester, (64)(2S)-3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.4-methoxyphenethyl ester, (65)(2S)-3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid is3-(4-methoxyphenyl)propyl ester, (66)(2S)-3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.furan-2-ylmethyl ester, (67)(2S)-3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acidthiophen-2-ylmethyl ester, (68)(2S)-3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid4-(4-methoxyphenyl)butyl ester, (69)(2S)-3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.cyclohexyl ester, (70)(2S)-3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acidmethyl ester, (71)(2S)-N-(4-methoxyphenyl)-3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanamide,(72) (2S)-3-cyclobutyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid4-methoxybenzyl ester, (73)(2S)-3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanoic aciddiphenylmethyl ester, (74)(2S)-N-((1S)-2-phenyl-1-benzyloxycarbonylethyl)-3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanamide,(75) (2S)-N-((1S)-1-benzyloxycarbonylethyl)-3-cyclohexyloxycarbonyl-2-tbutoxycarbonylaminopropanamide, (76)(2S)-3-benzyloxycarbonyl-2-t-butoxycarbonylaminopropanoic acid4-methoxybenzyl ester, (77)(2S)-3-cycloheptyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.4-methoxybenzyl ester, (78)(2S)-3-cyclooctyloxycarbonyl-2-t-butoxycarbonylaminopropanoicacid.4-methoxybenzyl ester, (79)(2S)-3-(adamantan-2-yloxycarbonyl)-2-t-butoxycarbonylaminopropanoicacid.4-methoxybenzyl ester, (80)(2S)-3-(adamantan-1-yloxycarbonyl)-2-t-butoxycarbonylaminopropanoicacid.4-methoxybenzyl ester, (81)(2S)-N-((1S)-1-(4-methoxybenzyloxycarbonyl)ethyl)-3-cyclohexyloxycarbonyl-2-benzyloxycarbonylaminopropanamide,(82) (2S)-N-((1S)-2-phenyl-1-(4-methoxybenzyloxycarbonyl)ethyl)-3-.cyclohexyloxycarbonyl-2-benzyloxycarbonylaminopropanamide, (83)(3S)-3-t-butoxycarbonylamino-3-(1, 2, 3,4-tetrahydroquinolin-1-ylcarbonyl)propanoic acid.cyclohexyl ester, (84)(3S)-3-t-butoxycarbonylamino-3-(1, 2, 3,4-tetrahydroisoquinolin-2-ylcarbonyl)propanoic acid.cyclohexyl ester,(85)(2S)-N-methyl-N-(1,1-dimethyl-2-phenylethyl)-3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanamide,(86)(2S)-N-((1S)-1-carboxy-2-phenylethyl)-3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanamide,(87)(2S)-N-((1S)-1-carboxyethyl)-3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanamide,(88)(2S)-N-((1S)-1-(4-methoxybenzyloxycarbonyl)ethyl)-3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanamide,(89) (2S)-N-((lS)-2-phenyl-1-(4-methoxybenzyloxycarbonyl)ethyl)-3-cyclohexyloxycarbonyl-2-t-butoxycarbonylaminopropanamide,(90) (2S)-3-cyclopentyloxycarbonyl-2-methylcarbonylaminopropanoic acid4-methoxybenzyl ester, (91)(2S)-3-cyclopentyloxycarbonyl-2-benzoylaminopropanoicacid.4-methoxybenzyl ester, (92)(2S)-3-cyclopentyloxycarbonyl-2-pivaloylaminopropanoicacid.4-methoxybenzyl ester, (93)(2S)-3-cyclopentyloxycarbonyl-2-cinnamoylaminopropanoicacid.4-methoxybenzyl ester, (94)(2S)-3-cyclopentyloxycarbonyl-2-valerylaminopropanoicacid.4-methoxybenzyl ester, (95)(2S)-3-cyclopentyloxycarbonyl-2-(octylcarbonylamino)propanoic acid4-methoxybenzyl ester, (96)(2S)-3-cyclopentyloxycarbonyl-2-mesylaminopropanoic acid 4-methoxybenzylester, (97) (2S)-3-cyclopentyloxycarbonyl-2-phenylsulfonylaminopropanoicacid.4-methoxybenzyl ester, (98)(2S)-3-cyclopentyloxycarbonyl-2-(butylsulfonylamino)propanoicacid.4-methoxybenzyl ester, (99)(2S)-3-cyclopentyloxycarbonyl-2-(octylsulfonylamino)propanoicacid.4-methoxybenzyl ester, (100)(2S)-3-cyclopentyloxycarbonyl-2-((E)-styrylsuflonylamino)propanoicacid.4-methoxybenzyl ester, (101)(2S)-3-cyclopentyloxycarbonyl-2-benzyloxycarbonylaminopropanoicacid.4-methoxybenzyl ester, (102)(2S)-3-cyclohexyloxycarbonyl-2-benzoylaminopropanoicacid.4-methoxybenzyl ester, (103)(2S)-3-cyclohexyloxycarbonyl-2-(4-fluorobenzoylamino)propanoicacid.4-methoxybenzyl ester, (104)(2S)-3-cyclohexyloxycarbonyl-2-(4-methoxybenzoyl)propanoic acid4-methoxybenzyl ester, (105)(2S)-3-cyclohexyloxycarbonyl-2-(4-phenylbenzoylamino)propanoicacid.4-methoxybenzyl ester, (106)(2S)-3-cyclohexyloxycarbonyl-2-(4-nitrobenzoylamino)propanoicacid.4-methoxybenzyl ester, (107)(2S)-3-cyclohexyloxycarbonyl-2-(4-acetylbenzoylamino)propanoicacid.4-methoxybenzyl ester, (108)(2S)-3-cyclohexyloxycarbonyl-2-(4-methylthiobenzoylamino)propanoicacid.4-methoxybenzyl ester, (109)(2S)-3-cyclohexyloxycarbonyl-2-(4-dimethylaminobenzoylamino)propanoicacid.4-methoxybenzyl ester, (110)(2S)-N-((1S)-1-carboxyethyl)-3-cyclohexyloxycarbonyl-2-benzyloxycarbonylaminopropanamide,(111)(2S)-N-((1S)-2-phenyl-1-carboxyethyl)-3-cyclohexyloxycarbonyl-2-benzyloxycarbonylaminopropanamide,(112)(2S)-3-cyclohexyloxycarbonyl-2-(N-benzyl-N-t-butoxycarbonylamino)propanoicacid.4-methoxybenzyl ester, or (113)(2S)-3-cyclohexyloxycarbonyl-2-benzylaminopropanoic acid 4-methoxybenzylester, or a non-toxic salt thereof, or a hydrate thereof.
 12. A compoundaccording to claim 8, which is (1)(2S)-3-cyclohexylcarbamoyl-2-t-butoxycarbonylaminopropanoic acid.benzylester, (2) (2S)-3-cyclopentylcarbamoyl-2-t-butoxycarbonylaminopropanoicacid.benzyl ester, (3)(2S)-4-(pyrrolidin-1-ylcarbonyl)-2-t-butoxycarbonylaminobutanoicacid.benzyl ester, (4)(2S)-3-cyclohexylcarbamoyl-2-t-butoxycarbonylaminopropanoic acid4-methoxybenzyl ester, (5)(2S)-N-(4-methoxybenzyl)-3-cyclohexylcarbamoyl-2-t-butoxycarbonylaminopropanamide,(6) (2S)-3-cyclopentylcarbamoyl-2-t-butoxycarbonylaminopropanoicacid.4-methoxybenzyl ester, (7)(2S)-N-(4-methoxybenzyl)-3-cyclopentylcarbamoyl-2-t-butoxycarbonylaminopropanamide,(8) (2S)-4-(pyrrolidin-1-ylcarbonyl)-2-t-butoxycarbonylaminobutanoicacid.4-methoxybenzyl ester, (9)(2S)-3-cyclohexylcarbonyloxy-2-t-butoxycarbonylaminopropanoicacid.4-methoxybenzyl ester, (10) (2S,3R)-3-cyclohexylcarbonyloxy-2-t-butoxycarbonylaminobutanoicacid.4-methoxybenzyl ester, (11)(2S)-6-cyclohexylcarbonylamino-2-t-butoxycarbonylaminohexanoicacid.4-methoxybenzyl ester, (12)(2S)-N-(4-methoxybenzyl)-3-cyclohexylcarbonylamino-2-t-butoxycarbonylaminopropanamide,(13) (2S)-4-cyclopentylamino-2-t-butoxycarbonylaminobutanoic acid4-methoxybenzyl ester, (14)(2S)-N-(4-methoxybenzyl)-3-cyclohexylsulfonylamino-2-t-butoxycarbonylaminopropanamide,or (15)(2R)-N-(4-methoxybenzyl)-3-cyclohexylsulfamoyl-2-t-butoxycarbonylaminopropanamide,or a non-toxic salt thereof, or a hydrate thereof.